Pyrimidine diol amides as sodium channel blockers

ABSTRACT

The present disclosure provides pyrimidine diol amides of Formula (I), and the pharmaceutically acceptable solvates and prodrugs thereof, wherein A 1 , X, A 2 , W 1 , W 2 , W 3 , R 1 , R 2 , and R 4  are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula (I) to treat a disorder responsive to the blockade of sodium channels. Compounds of the present disclosure are especially useful for treating pain.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 14/358,155, filed on May 14, 2014, with a §371 date of May 14,2014, allowed, which is the U.S. national phase, pursuant to 35 U.S.C.§371, of PCT International Application Ser. No. PCT/IB2012/002504, filedNov. 14, 2012, designating the United States and published in English onMay 23, 2013 as PCT Publication No. WO 2013/072758 A1, claiming priorityto U.S. Provisional Application Ser. No. 61/560,092, filed Nov. 15,2011. The contents of the afore-mentioned patent applications areincorporated herein by their entirety.

BACKGROUND OF THE INVENTION

Field of the Invention

This invention is in the field of medicinal chemistry. The inventionprovides novel pyrimidine diol amides and the use of these compounds asblockers of voltage-gated sodium (Na⁺) channels.

Background Art

Voltage-gated sodium channels (VGSCs) are found in all excitable cells.Sodium channels are primarily responsible for generating the rapidupstroke of the action potential in neuronal cells of the centralnervous system (CNS) and peripheral nervous system (PNS). In this mannersodium channels are essential to the initiation and propagation ofelectrical signals in the nervous system. Proper function of sodiumchannels is therefore necessary for normal function of the neuron.Consequently, aberrant sodium channel function is thought to underlie avariety of medical disorders (See Hubner et al., Hum. Mol. Genet.11:2435-2445 (2002) for a general review of inherited ion channeldisorders) including epilepsy (Yogeeswari et al, Curr. Drug Target5:589-602 (2004)), arrhythmia (Noble, Proc. Natl. Acad. Sci. USA99:5755-5756 (2002)), myotonia (Cannon, Kidney Int. 57:772-779 (2000)),and pain (Wood et al., J. Neurobiol., 61:55-71 (2004)).

VGSCs are composed of one α-subunit, which forms the core of the channeland is responsible for voltage-dependent gating and ion permeation, andseveral auxiliary β-subunits (see, e.g., Chahine et al., CNS &Neurological Disorders-Drug Targets 7:144-158 (2008) and Kyle and Ilyin,J. Med. Chem. 50:2583-2588 (2007)). α-Subunits are large proteinscomposed of four homologous domains. Each domain contains six α-helicaltransmembrane spanning segments. There are currently nine known membersof the family of voltage-gated sodium channel α-subunits. Names for thisfamily include SCNx, SCNAx, and Na_(v)x.x (see Table 1, below). The VGSCfamily has been phylogenetically divided into two subfamilies Na_(v)1.x(all but SCN6A) and Na_(v)2.x (SCN6A). The Na_(v)1.x subfamily can befunctionally subdivided into two groups, those which are sensitive toblocking by tetrodotoxin (TTX-sensitive or TTX-s) and those which areresistant to blocking by tetrodotoxin (TTX-resistant or TTX-r).

There are three members of the subgroup of TTX-resistant sodiumchannels. The SCN5A gene product (Na_(v)1.5, HL) is almost exclusivelyexpressed in cardiac tissue and has been shown to underlie a variety ofcardiac arrhythmias and other conduction disorders (Liu et al., Am. J.Pharmacogenomics 3:173-179 (2003)). Consequently, blockers of Na_(v)1.5have found clinical utility in treatment of such disorders (Srivatsa etal., Curr. Cardiol. Rep. 4:401-410 (2002)). The remaining TTX-resistantsodium channels, Na_(v)1.8 (SCN10A, PN3, SNS) and Na_(v)1.9 (SCN11A,NaN, SNS2) are expressed in the peripheral nervous system and showpreferential expression in primary nociceptive neurons. Human geneticvariants of these channels have not been associated with any inheritedclinical disorder. However, aberrant expression of Na_(v)1.8 has beenfound in the CNS of human multiple sclerosis (MS) patients and also in arodent model of MS (Black et al., Proc. Natl. Acad. Sci. USA97:11598-115602 (2000)). Evidence for involvement in nociception is bothassociative (preferential expression in nociceptive neurons) and direct(genetic knockout). Na_(v)1.8-null mice exhibited typical nociceptivebehavior in response to acute noxious stimulation but had significantdeficits in referred pain and hyperalgesia (Laird et al., J. Neurosci.22:8352-8356 (2002)).

TABLE 1 Voltage-gated sodium channel gene family Gene TTX IC₅₀ DiseaseType Symbol Tissue Distribution (nM) Association Indications Na_(v)1.1SCN1A CNS/PNS 10 Epilepsy Pain, seizures, neurodegeneration Na_(v)1.2SCN2A CNS 10 Epilepsy Epilepsy, neurodegeneration Na_(v)1.3 SCN3A CNS 15— Pain Na_(v)1.4 SCN4A Skeletal muscle 25 Myotonia Myotonia Na_(v)1.5SCN5A Heart muscle 2,000 Arrhythmia Arrhythmia Na_(v)1.6 SCN8A CNS/PNS 6— Pain, movement disorders Na_(v)1.7 SCN9A PNS 25 Erythermalgia PainNa_(v)1.8 SCN10A PNS 50,000 — Pain Na_(v)1.9 SCN11A PNS 1,000 — Pain

The Na_(v)1.7 (PNI, SCN9A) VGSC is sensitive to blocking by tetrodotoxinand is preferentially expressed in peripheral sympathetic and sensoryneurons. The SCN9A gene has been cloned from a number of species,including human, rat, and rabbit and shows ˜90% amino acid identitybetween the human and rat genes (Toledo-Aral et al., Proc. Natl. Acad.Sci. USA 94:1527-1532 (1997)).

An increasing body of evidence suggests that Na_(v)1.7 plays a key rolein various pain states, including acute, inflammatory and/or neuropathicpain. Deletion of the SCN9A gene in nociceptive neurons of mice led toan increase in mechanical and thermal pain thresholds and reduction orabolition of inflammatory pain responses (Nassar et al., Proc. Natl.Acad. Sci. USA 101:12706-12711 (2004)).

Sodium channel-blocking agents have been reported to be effective in thetreatment of various disease states, and have found particular use aslocal anesthetics, e.g., lidocaine and bupivacaine, and in the treatmentof cardiac arrhythmias, e.g., propafenone and amiodarone, and epilepsy,e.g., lamotrigine, phenytoin and carbamazepine (see Clare et al., DrugDiscovery Today 5:506-510 (2000); Lai et al., Annu. Rev. Pharmacol.Toxicol. 44:371-397 (2004); Anger et al., J. Med. Chem. 44:115-137(2001), and Catterall, Trends Pharmacol. Sci. 8:57-65 (1987)). Each ofthese agents is believed to act by interfering with the rapid influx ofsodium ions.

Other sodium channel blockers such as BW619C89 and lifarizine have beenshown to be neuroprotective in animal models of global and focalischemia (Graham et al., J. Pharmacol. Exp. Ther. 269:854-859 (1994);Brown et al., British J. Pharmacol. 115:1425-1432 (1995)).

It has also been reported that sodium channel-blocking agents can beuseful in the treatment of pain, including acute, chronic, inflammatory,neuropathic, and other types of pain such as rectal, ocular, andsubmandibular pain typically associated with paroxysmal extreme paindisorder; see, for example, Kyle and Ilyin., J. Med. Chem. 50:2583-2588(2007); Wood et al., J. Neurobiol. 61:55-71 (2004); Baker et al., TRENDSin Pharmacological Sciences 22:27-31 (2001); and Lai et al., CurrentOpinion in Neurobiology 13:291-297 (2003); the treatment of neurologicaldisorders such as epilepsy, seizures, epilepsy with febrile seizures,epilepsy with benign familial neonatal infantile seizures, inheritedpain disorders, e.g., primary erthermalgia and paroxysmal extreme paindisorder, familial hemiplegic migraine, and movement disorder; and thetreatment of other psychiatric disorders such as autism, cerebellaratrophy, ataxia, and mental retardation; see, for example, Chahine etal., CNS & Neurological Disorders-Drug Targets 7:144-158 (2008) andMeisler and Kearney, J. Clin. Invest. 115:2010-2017 (2005). In additionto the above-mentioned clinical uses, carbamazepine, lidocaine andphenytoin are used to treat neuropathic pain, such as from trigeminalneuralgia, diabetic neuropathy and other forms of nerve damage (Taylorand Meldrum, Trends Pharmacol. Sci. 16:309-316 (1995)). Furthermore,based on a number of similarities between chronic pain and tinnitus,(Moller, Am. J. Otol. 18:577-585 (1997); Tonndorf, Hear. Res. 28:271-275(1987)) it has been proposed that tinnitus should be viewed as a form ofchronic pain sensation (Simpson, et al., Tip. 20:12-18 (1999)). Indeed,lidocaine and carbamazepine have been shown to be efficacious intreating tinnitus (Majumdar, B. et al., Clin. Otolaryngol. 8:175-180(1983); Donaldson, Laryngol. Otol. 95:947-951 (1981)).

Many patients with either acute or chronic pain disorders respond poorlyto current pain therapies, and the development of resistance orinsensitivity to opiates is common. In addition, many of the currentlyavailable treatments have undesirable side effects.

In view of the limited efficacy and/or unacceptable side-effects of thecurrently available agents, there is a pressing need for more effectiveand safer analgesics that work by blocking sodium channels.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present disclosure provides pyrimidine diol amidesrepresented by Formulae I-VIII, below, and the pharmaceuticallyacceptable solvates and prodrugs thereof, collectively referred toherein as “Compounds of the Invention.”

In another aspect, the present disclosure provides the use of Compoundsof the Invention as blockers of sodium (Na⁺) channels.

In another aspect, the present disclosure provides a method for treatinga disorder responsive to the blockade of sodium channels in a mammal,comprising administering to the mammal an effective amount of a Compoundof the Invention.

In another aspect, the present disclosure provides a method for treatingpain (e.g., acute pain, chronic pain, which includes but is not limitedto, neuropathic pain, postoperative pain, and inflammatory pain, orsurgical pain), comprising administering an effective amount of aCompound of the Invention to a mammal in need of such treatment.Specifically, the present disclosure provides a method for preemptive orpalliative treatment of pain by administering an effective amount of aCompound of the Invention to a mammal in need of such treatment.

In another aspect, the present disclosure provides a method for treatingstroke, neuronal damage resulting from head trauma, epilepsy, seizures,general epilepsy with febrile seizures, severe myoclonic epilepsy ininfancy, neuronal loss following global and focal ischemia, migraine,familial primary erythromelalgia, paroxysmal extreme pain disorder,cerebellar atrophy, ataxia, dystonia, tremor, mental retardation,autism, a neurodegenerative disorder (e.g., Alzheimer's disease,amyotrophic lateral sclerosis (ALS), or Parkinson's disease), manicdepression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia, comprising administering aneffective amount of a Compound of the Invention to a mammal in need ofsuch treatment.

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising a Compound of the Invention and one or morepharmaceutically acceptable carriers.

In another aspect, the present disclosure provides a pharmaceuticalcomposition for treating a disorder responsive to the blockade of sodiumion channels, wherein the pharmaceutical composition comprises aneffective amount of a Compound of the Invention in a mixture with one ormore pharmaceutically acceptable carriers.

In another aspect, the present disclosure provides a method ofmodulating sodium channels in a mammal, comprising administering to themammal an effective amount of at least one Compound of the Invention.

In another aspect, the present disclosure provides Compounds of theInvention for use in treating pain in a mammal, e.g., acute pain,chronic pain, which includes but is not limited to, neuropathic pain,postoperative pain, and inflammatory pain, or surgical pain.

In another aspect, the present disclosure provides Compounds of theInvention for use in treating stroke, neuronal damage resulting fromhead trauma, epilepsy, seizures, general epilepsy with febrile seizures,severe myoclonic epilepsy in infancy, neuronal loss following global andfocal ischemia, migraine, familial primary erythromelalgia, paroxysmalextreme pain disorder, cerebellar atrophy, ataxia, dystonia, tremor,mental retardation, autism, a neurodegenerative disorder (e.g.,Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or Parkinson'sdisease), manic depression, tinnitus, myotonia, a movement disorder, orcardiac arrhythmia, or providing local anesthesia, in a mammal.

In another aspect, the present disclosure provides a radiolabeledCompound of the Invention and the use of such compounds as radioligandsin any appropriately selected competitive binding assays and screeningmethodologies. Thus, the present disclosure further provides a methodfor screening a candidate compound for its ability to bind to a sodiumchannel or sodium channel subunit using a radiolabeled Compound of theInvention. In certain embodiments, the compound is radiolabeled with ³H,¹¹C, or ¹⁴C. This competitive binding assay can be conducted using anyappropriately selected methodology. In one embodiment, the screeningmethod comprises: i) introducing a fixed concentration of theradiolabeled compound to an in vitro preparation comprising a soluble ormembrane-associated sodium channel, subunit or fragment under conditionsthat permit the radiolabeled compound to bind to the channel, subunit orfragment, respectively, to form a conjugate; ii) titrating the conjugatewith a candidate compound; and iii) determining the ability of thecandidate compound to displace the radiolabeled compound from saidchannel, subunit or fragment.

In another aspect, the present disclosure provides a Compound of theInvention for use in the manufacture of a medicament for treating painin a mammal. In one embodiment, the present disclosure provides the useof a Compound of the Invention in the manufacture of a medicament forpalliative or preemptive treatment of pain, such as acute pain, chronicpain, or surgical pain.

In another aspect, the present disclosure provides a Compound of theInvention for use in the manufacture of a medicament for treatingstroke, neuronal damage resulting from head trauma, epilepsy, seizures,general epilepsy with febrile seizures, severe myoclonic epilepsy ininfancy, neuronal loss following global and focal ischemia, migraine,familial primary erythromelalgia, paroxysmal extreme pain disorder,cerebellar atrophy, ataxia, dystonia, tremor, mental retardation,autism, a neurodegenerative disorder (e.g., Alzheimer's disease,amyotrophic lateral sclerosis (ALS), or Parkinson's disease), manicdepression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia, in a mammal.

Additional embodiments and advantages of the disclosure will be setforth, in part, in the description that follows, and will flow from thedescription, or can be learned by practice of the disclosure. Theembodiments and advantages of the disclosure will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is to be understood that both the foregoing summary and the followingdetailed description are exemplary and explanatory only, and are notrestrictive of the invention as claimed.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present disclosure is based on the use of Compounds ofthe Invention as blockers of Na⁺ channels. In view of this property,Compounds of the Invention are useful for treating disorders responsiveto the blockade of sodium ion channels.

In one embodiment, Compounds of the Invention are compounds representedby Formula I:

and the pharmaceutically acceptable salts, solvates, or prodrugsthereof, wherein:

W¹ and W² are N and W³ is CR³; or

W¹ and W³ are N and W² is CR³; or

W² and W³ are N and W¹ is CR³;

R¹ is selected from the group consisting of hydrogen; optionallysubstituted alkyl; optionally substituted cycloalkyl; aralkyl;(heterocyclo)alkyl; (heteroaryl)alkyl; (amino)alkyl; (alkylamino)alkyl;(dialkylamino)alkyl; carboxyalkyl; (alkoxycarbonyl)alkyl;(carboxamido)alkyl; (cyano)alkyl; alkoxyalkyl; monohydroxyalkyl;dihydroxyalkyl; and heteroalkyl;

R² is selected from the group consisting of hydrogen and alkyl; or

R¹ and R² taken together with the nitrogen atom to which they areattached form a 3- to 8-membered optionally substituted heterocyclo;

R³ is selected from the group consisting of hydrogen; halo; nitro;cyano; hydroxy; amino; alkylamino; dialkylamino; haloalkyl;monohydroxyalkyl; dihydroxyalkyl; alkoxy; haloalkoxy; and alkoxyalkyl;

R⁴ is C₂₋₆ dihydroxyalkyl;

A¹ is selected from the group consisting of optionally substituted aryland optionally substituted heteroaryl, e.g., optionally substitutedphenyl and optionally substituted pyridyl;

X is selected from the group consisting of —O—; —S—; —SO—; —SO₂—;—(CR^(5a)R^(5b))_(m)—; —NR⁶—; —SO₂NR⁷—; and —NR⁷SO₂—;

each R^(5a) and R^(5b), which can be identical or different, is selectedfrom the group consisting of hydrogen; halo; and alkyl;

-   -   m is 0, 1, 2, or 3;

R⁶ is selected from the group consisting of hydrogen and alkyl;

R⁷ is selected from the group consisting of hydrogen and alkyl; and

A² is selected from the group consisting of optionally substituted aryland optionally substituted heteroaryl, e.g., optionally substitutedphenyl and optionally substituted pyridyl.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula II:

and the pharmaceutically acceptable salts, solvates, or prodrugsthereof, wherein:

R^(8a) and R^(8b) are each independently selected from the groupconsisting of hydrogen; alkyl; halo; nitro; cyano; hydroxy; amino;alkylamino; dialkylamino; haloalkyl; monohydroxyalkyl; dihydroxyalkyl;alkoxy; haloalkoxy; carboxy; and alkoxycarbonyl; and

A¹, X, W¹, W², W³, R¹, R², and R⁴ are as defined above in connectionwith Formula I.

In one embodiment, R^(8a) and R^(8b) are each independently selectedfrom the group consisting of hydrogen; alkyl; halo; cyano; andhaloalkyl.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula III:

and the pharmaceutically acceptable salts, solvates, or prodrugsthereof, wherein:

A¹, X, R^(8a), R^(8b), W¹, W², W³, R¹, R², and R⁴ are as defined abovein connection with Formulae I and II.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formulae I-III, and the pharmaceutically acceptablesalts, solvates, or prodrugs thereof, wherein:

X is selected from the group consisting of —O—; —S—; —SO₂—; —(CH₂)_(m)—;and —NH—;

m is 0 or 1; and

A¹, R^(8a), R^(8b), W¹, W², W³, R¹, R², and R⁴ are as defined above inconnection with Formulae I and II.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula IV:

and the pharmaceutically acceptable salts, solvates, or prodrugsthereof, wherein:

A¹, R^(8a), R^(8b), W¹, W², W³, R¹, R², and R⁴ are as defined above inconnection with Formulae I and II.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formulae I-IV, and the pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein A¹ is selected from the groupconsisting of:

wherein:

R^(9a), R^(9b), R^(10a), R^(10b), R^(11a), R^(11b), R^(12a), and R^(12b)are each independently selected from the group consisting of hydrogen;halo; nitro; cyano; hydroxy; amino; alkylamino; dialkylamino; haloalkyl;monohydroxyalkyl; dihydroxyalkyl; alkoxy; haloalkoxy; carboxy; andalkoxycarbonyl; and

A², X, R^(8a), R^(8b), W¹, W², W³, R¹, R², and R⁴ are as defined abovein connection with Formulae I and II.

In one embodiment, R^(9a), R^(9b), R^(10a), R^(10b), R^(11a), R^(11b),R^(12a), and R^(12b) are each independently selected from the groupconsisting of hydrogen; alkyl; halo; cyano; and haloalkyl.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formulae I-IV, and the pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

W¹ and W² are N and W³ is CR³;

R³ is selected from the group consisting of hydrogen and C₁₋₄ alkyl; and

A¹, A², X, R^(8a), R^(8b), R¹, R², and R⁴ are as defined above inconnection with Formulae I and II.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formulae I-IV, and the pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

W¹ and W³ are N and W² is CR³;

R³ is selected from the group consisting of hydrogen and C₁₋₄ alkyl; and

A¹, A², X, R^(8a), R^(8b), R¹, R², and R⁴ are as defined above inconnection with Formulae I and II.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formulae I-IV, and the pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

W² and W³ are N and W¹ is CR³;

R³ is selected from the group consisting of hydrogen and C₁₋₄ alkyl; and

A¹, A², X, R^(8a), R^(8b), R¹, R², and R⁴ are as defined above inconnection with Formulae I and II.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formulae II-IV, and the pharmaceutically acceptablesalts, solvates, or prodrugs thereof, wherein:

R^(8a) and R^(8b) are hydrogen; and

A¹, X, W¹, W², W³, R¹, R², and R⁴ are as defined above in connectionwith Formulae I and II.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formulae I-IV, and the pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R¹ is selected from the group consisting of hydrogen; alkyl;carboxyalkyl; (alkoxycarbonyl)alkyl; and (carboxamido)alkyl;

R² is hydrogen; and

A¹, A², X, R^(8a), R^(8b), W¹, W², W³, and R⁴ are as defined above inconnection with Formulae I and II.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formulae I-IV, and the pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R¹ is selected from the group consisting of hydrogen and C₁₋₄ alkyl;

R² is hydrogen; and

A¹, A², X, R^(8a), R^(8b), W¹, W², W³, and R⁴ are as defined above inconnection with Formulae I and II.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formulae I-IV, and the pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R¹ and R² are each hydrogen; and

A¹, A², X, R^(8a), R^(8b), W¹, W², W³, and R⁴ are as defined above inconnection with Formulae I and II.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formulae I-IV, and the pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R⁴ is a C₂₋₄ dihydroxyalkyl; and

A¹, A², X, W¹, W², W³, R¹, and R² are as defined above in connectionwith Formulae I and II.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formulae I-IV, and the pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R⁴ is selected from the group consisting of:

A¹, A², X, W, W², W³, R¹, and R² are as defined above in connection withFormulae I and II.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formulae I-IV, and the pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R⁴ is:

A¹, A², X, W¹, W², W³, R¹, and R² are as defined above in connectionwith Formulae I and II.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formulae I-IV, and the pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R⁴ is:

and

A¹, A², X, W¹, W², W³, R¹, and R² are as defined above in connectionwith Formulae I and II.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula V:

and the pharmaceutically acceptable salts, solvates, or prodrugsthereof, wherein A¹ is defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula VI:

and the pharmaceutically acceptable salts, solvates, or prodrugsthereof, wherein A¹ is defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula VII:

and the pharmaceutically acceptable salts, solvates, or prodrugsthereof, wherein A¹ is defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula VIII:

and the pharmaceutically acceptable salts, solvates, or prodrugsthereof, wherein A¹ is defined above in connection with Formula I.

In another embodiment, compounds of the invention are compoundsrepresented by Formulae V or VI, and the pharmaceutically acceptablesalts, solvates, or prodrugs thereof, wherein A¹ is selected from thegroup consisting of A¹-1 and A¹-2.

In another embodiment, compounds of the invention are compoundsrepresented by Formulae VII or VIII, and the pharmaceutically acceptablesalts, solvates, or prodrugs thereof, wherein A¹ is selected from thegroup consisting of A¹-1 and A¹-2.

In another embodiment, compounds of the invention are compoundsrepresented by Formulae V or VI, and the pharmaceutically acceptablesalts, solvates, or prodrugs thereof, wherein A¹ is A¹-2.

In another embodiment, compounds of the invention are compoundsrepresented by Formulae VII or VIII, and the pharmaceutically acceptablesalts, solvates, or prodrugs thereof, wherein A¹ is A¹-2.

In another embodiment, compounds of the invention are compoundsrepresented by Formulae V or VI, and the pharmaceutically acceptablesalts, solvates, or prodrugs thereof, wherein:

A¹ is A¹-2; and

R^(10a) and R^(10b) are each independently selected from the groupconsisting of hydrogen; alkyl; halo; cyano; and haloalkyl.

In another embodiment, compounds of the invention are compoundsrepresented by Formulae VII or VIII, and the pharmaceutically acceptablesalts, solvates, or prodrugs thereof, wherein:

A¹ is A¹-2; and

R^(10a) and R^(10b) are each independently selected from the groupconsisting of hydrogen; alkyl; halo; cyano; and haloalkyl.

In another embodiment, compounds of the invention are compoundsrepresented by Formulae V or VI, and the pharmaceutically acceptablesalts, solvates, or prodrugs thereof, wherein A¹ is A¹-1.

In another embodiment, compounds of the invention are compoundsrepresented by Formulae VII or VIII, and the pharmaceutically acceptablesalts, solvates, or prodrugs thereof, wherein A¹ is A¹-1.

In another embodiment, compounds of the invention are compoundsrepresented by Formulae V or VI, and the pharmaceutically acceptablesalts, solvates, or prodrugs thereof, wherein:

A¹ is A¹-1; and

R^(9a) and R^(9b) are each independently selected from the groupconsisting of hydrogen; alkyl; halo; cyano; and haloalkyl.

In another embodiment, compounds of the invention are compoundsrepresented by Formulae VII or VIII, and the pharmaceutically acceptablesalts, solvates, or prodrugs thereof, wherein:

A¹ is A¹-1; and

R^(9a) and R^(9b) are each independently selected from the groupconsisting of hydrogen; alkyl; halo; cyano; and haloalkyl.

In another embodiment, Compounds of the Invention are compounds of TABLE2, and the pharmaceutically acceptable salts, solvates and prodrugsthereof.

TABLE 2 Compound Example No. Structure  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

The chemical names of the compound examples are provided in TABLE 3.

TABLE 3 Compound Example No. Chemical Name 1(S)-6-(1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide 2(R)-6-(1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide 3(S)-2-(4-(4-cyanophenoxy)phenyl-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide 4(R)-2-(4-(4-cyanophenoxy)phenyl-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide 5(S)-2-(4-(4-cyano-2-(trifluoromethyl)phenoxy)phenyl-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide 6(R)-2-(4-(4-cyano-2-(trifluoromethyl)phenoxy)phenyl-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide 7(R)-2-(4-(5-chloro-2-fluorophenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide 8(S)-2-(4-(5-chloro-2-fluorophenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide 9(R)-2-(4-(4-chloro-2-fluorophenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide 10(S)-2-(4-(4-chloro-2-fluorophenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide 11(S)-2-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide 12(R)-2-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide 13(S)-2-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide 14 (S)-methyl2-(6-((S)-1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamido)propanoate 15(S)-2-(6-((S)-1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamido)propanoic acid 16N-((S)-1-amino-1-oxopropan-2-yl)-6-((S)-1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4- carboxamide17 (S)-6-(1,2-dihydroxyethyl)-2-(4-(4-(trifluoromethyl)phenoxy)phenyl)pyrimidine-4-carboxamide 18(R)-6-(1,2-dihydroxyethyl)-2-(4-(4-(trifluoromethyl)phenoxy)phenyl)pyrimidine-4-carboxamide 19(S)-6-(1,2-dihydroxyethyl)-2-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)pyrimidine-4-carboxamide 20(R)-4-(1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)pyrimidine-2-carboxamide 21(S)-4-(1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)pyrimidine-2-carboxamide

For the purpose of the present disclosure, the term “alkyl” as used byitself or as part of another group refers to a straight- orbranched-chain aliphatic hydrocarbon containing 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, or 12 carbon atoms (i.e., C₁₋₁₂ alkyl) or the number ofcarbon atoms designated (i.e., a C₁ alkyl such as methyl, a C₂ alkylsuch as ethyl, a C₃ alkyl such as propyl or isopropyl, etc.). In oneembodiment, the alkyl group is chosen from a straight chain C₁₋₁₀ alkylgroup. In another embodiment, the alkyl group is chosen from a branchedchain C₁₋₁₀ alkyl group. In another embodiment, the alkyl group ischosen from a straight chain C₁₋₆ alkyl group. In another embodiment,the alkyl group is chosen from a branched chain C₁₋₆ alkyl group. Inanother embodiment, the alkyl group is chosen from a straight chain C₁₋₄alkyl group. In another embodiment, the alkyl group is chosen from abranched chain C₃₋₄ alkyl group. In another embodiment, the alkyl groupis chosen from a straight or branched chain C₂₋₆ alkyl group. In anotherembodiment, the alkyl group is chosen from a straight or branched chainC₂₋₄ alkyl group. Non-limiting exemplary C₁₋₁₀alkyl groups includemethyl, ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl,-n-octyl, -n-nonyl, and -n-decyl, isopropyl, sec-butyl, tert-butyl,iso-butyl, -iso-pentyl, -neopentyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl,2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl,4-methylhexyl, 5-methylhexyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl,1,2-dimethylhexyl, 1,3-dimethylhexyl, 3,3-dimethylhexyl,1,2-dimethylheptyl, 1,3-dimethylheptyl, and 3,3-dimethylheptyl.Non-limiting exemplary C1-4 alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, tert-butyl, and iso-butyl.

For the purpose of the present disclosure, the term “optionallysubstituted alkyl” as used by itself or as part of another group meansthat the alkyl as defined above is either unsubstituted or substitutedwith one, two, or three substituents independently chosen from nitro,haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl,arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, andcycloalkyl. In one embodiment, the optionally substituted alkyl issubstituted with two substituents. In another embodiment, the optionallysubstituted alkyl is substituted with one substituent. Non-limitingexemplary optionally substituted alkyl groups include —CH₂CH₂NO₂,—CH₂CH₂CO₂H, —CH₂CH₂SO₂CH₃, —CH₂CH₂COPh, and —CH₂C₆H₁₁.

For the purpose of the present disclosure, the term “cycloalkyl” as usedby itself or as part of another group refers to saturated and partiallyunsaturated (containing e.g. one or two double bonds) cyclic aliphatichydrocarbons containing one, two or three rings having from 3, 4, 5, 6,7, 8, 9, 10, 11, or 12 carbon atoms (i.e., C₃₋₁₂ cycloalkyl) or thenumber of carbons designated. In one embodiment, the cycloalkyl grouphas two rings. In one embodiment, the cycloalkyl group has one ring. Inanother embodiment, the cycloalkyl group is chosen from a C₃₋₈cycloalkyl group. In another embodiment, the cycloalkyl group is chosenfrom a C₃₋₆ cycloalkyl group. Non-limiting exemplary cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl,norbornyl, decalin, adamantyl, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctenyl,cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl, cyclononenyl,cyclononadienyl, cyclononatrienyl, cyclodecenyl, cyclodecadienyl,cyclotetradecenyl, and cyclododecadienyl.

For the purpose of the present disclosure, the term “optionallysubstituted cycloalkyl” as used by itself or as part of another groupmeans that the cycloalkyl as defined above is either unsubstituted orsubstituted with one, two, or three substituents independently chosenfrom halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino,haloalkyl, monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy,aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl,arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy,carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino,(alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and(heteroaryl)alkyl. In one embodiment, the optionally substitutedcycloalkyl is substituted with two substituents. In another embodiment,the optionally substituted cycloalkyl is substituted with onesubstituent. Non-limiting exemplary optionally substituted cycloalkylgroups include:

For the purpose of the present disclosure, the term “alkenyl” as used byitself or as part of another group refers to an alkyl group having 2, 3,4, 5, 6, 7, 8, 9, or 10 carbon atoms (C₂₋₁₀alkenyl) and including atleast one, e.g. one, two or three, carbon-carbon double |[Al]bond. Inone embodiment, the alkenyl group is chosen from a C₂₋₆ alkenyl group.In another embodiment, the alkenyl group is chosen from a C₂₋₄ alkenylgroup. Non-limiting exemplary alkenyl groups include ethenyl, propenyl,isopropenyl, butenyl, sec-butenyl, -iso-butylenyl, -1-pentenyl,-2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl,-2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl,-1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl,-3-octenyl, -1-nonenyl, -2-nonenyl, -3-nonenyl, -1-decenyl, -2-decenyl,-3-decenyl, and the like.

For the purpose of the present disclosure, the term “optionallysubstituted alkenyl” as used herein by itself or as part of anothergroup means the alkenyl as defined above is either unsubstituted orsubstituted with one, two or three substituents independently chosenfrom halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino,haloalkyl, monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy,aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl,arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy,carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, orheterocyclo.

For the purpose of the present disclosure, the term “alkynyl” as used byitself or as part of another group refers to an alkyl group having 2, 3,4, 5, 6, 7, 8, 9, or 10 carbon atoms ((C₂₋₁₀)alkynyl) and including atleast one, e.g. one, two or three, carbon-carbon triple bond. In oneembodiment, the alkynyl has one carbon-to-carbon triple bond. In oneembodiment, the alkynyl group is chosen from a C₂₋₆ alkynyl group. Inanother embodiment, the alkynyl group is chosen from a C₂₋₄ alkynylgroup. Non-limiting exemplary alkynyl groups include ethynyl, propynyl,1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, -3-methyl-1-butynyl,-4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl, -1-heptynyl,-2-heptynyl, -6-heptynyl, -1-octynyl, -2-octynyl, -7-octynyl,-1-nonynyl, -2-nonynyl, -8-nonynyl, -1-decynyl, -2-decynyl, -9-decynyl,and the like.

For the purpose of the present disclosure, the term “optionallysubstituted alkynyl” as used herein by itself or as part of anothergroup means the alkynyl as defined above is either unsubstituted orsubstituted with one, two or three substituents independently chosenfrom halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino,haloalkyl, monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy,aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl,arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy,carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, orheterocyclo.

For the purpose of the present disclosure, the term “haloalkyl” as usedby itself or as part of another group refers to an alkyl groupsubstituted by one or more fluorine, chlorine, bromine and/or iodineatoms. In one embodiment, the alkyl group is substituted by one, two, orthree fluorine and/or chlorine atoms. In another embodiment, thehaloalkyl group is chosen from a C₁₋₄ haloalkyl group. Non-limitingexemplary haloalkyl groups include fluoromethyl, difluoromethyl,trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, andtrichloromethyl groups.

For the purpose of the present disclosure, the term “monohydroxyalkyl”as used by itself or as part of another group refers to an alkyl groupas defined above substituted with exactly one hydroxy group.Non-limiting exemplary monohydroxyalkyl groups include hydroxymethyl,hydroxyethyl, hydroxypropyl and hydroxybutyl groups. In one embodiment,the monohydroxyalkyl group is a C₁₋₆ monohydroxyalkyl. In oneembodiment, the monohydroxyalkyl group is a C₁₋₄ monohydroxyalkyl.

For the purpose of the present disclosure, the term “dihydroxyalkyl” asused by itself or as part of another group refers to an alkyl group asdefined above substituted with exactly two hydroxy groups. Non-limitingexemplary dihydroxyalkyl groups include 1,2-dihydroxyethyl and1,3-dihydroxyprop-2-yl. In one embodiment, the dihydroxyalkyl group is aC₂₋₆ dihydroxyalkyl. In one embodiment, the dihydroxyalkyl group is aC₂₋₄ dihydroxyalkyl. In one embodiment, the dihydroxyalkyl group is a C₂dihydroxyalkyl.

For the purpose of the present disclosure, the term “alkoxy” as used byitself or as part of another group refers to an optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substituted alkenylor optionally substituted alkynyl attached to a terminal oxygen atom. Inone embodiment, the alkoxy group is chosen from a C₁₋₆ alkoxy group. Inanother embodiment, the alkoxy group is chosen from a C₁₋₄ alkylattached to a terminal oxygen atom, e.g., methoxy, ethoxy, andtert-butoxy.

For the purpose of the present disclosure, the term “alkylthio” as usedby itself or as part of another group refers to a sulfur atomsubstituted by an optionally substituted alkyl group. In one embodiment,the alkylthio group is chosen from a C₁₋₄ alkylthio group. Non-limitingexemplary alkylthio groups include —SCH₃, and —SCH₂CH₃.

For the purpose of the present disclosure, the term “alkoxyalkyl” asused by itself or as part of another group refers to an alkyl groupsubstituted with an alkoxy group. Non-limiting exemplary alkoxyalkylgroups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl,ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl,iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl,tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, andpentyloxymethyl.

For the purpose of the present disclosure, the term “heteroalkyl” asused by itself or part of another group refers to a stable straight orbranched chain hydrocarbon radical containing 1, 2, 3, 4, 5, 6, 7, 8, 9,or 10 carbon atoms and at least two heteroatoms, which can be the sameor different, selected from O, N, or S, wherein: 1) the nitrogen atom(s)and sulfur atom(s) can optionally be oxidized (to yield an N-oxide,sulfoxide or sulfone); and/or 2) the nitrogen atom(s) can optionally bequaternized. The heteroatoms can be placed at any interior position ofthe heteroalkyl group or at a position at which the heteroalkyl group isattached to the remainder of the molecule. In one embodiment, theheteroalkyl group contains two oxygen atoms. Non-limiting exemplaryheteroalkyl groups include —CH₂OCH—₂CH₂OCH₃, —OCH₂CH₂OCH₂CH₂OCH₃,—CH₂NHCH₂CH₂OCH₂, —OCH₂CH₂NH₂, and —NHCH₂CH₂N(H)CH₃.

For the purpose of the present disclosure, the term “haloalkoxy” as usedby itself or as part of another group refers to a haloalkyl attached toa terminal oxygen atom. Non-limiting exemplary haloalkoxy groups includefluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, and2,2,2-trifluoroethoxy.

For the purpose of the present disclosure, the term “aryl” as used byitself or as part of another group refers to a monocyclic or bicyclicaromatic ring system having from six to fourteen carbon atoms (i.e.,C₆₋₁₄ aryl). Non-limiting exemplary aryl groups include phenyl(abbreviated as “Ph”), naphthyl, phenanthryl, anthracyl, indenyl,azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In oneembodiment, the aryl group is chosen from phenyl or naphthyl.

For the purpose of the present disclosure, the term “optionallysubstituted aryl” as used herein by itself or as part of another groupmeans that the aryl as defined above is either unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents independently chosen fromhalo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl,monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy, aryloxy,aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl,arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy,carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino,(alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, or(heteroaryl)alkyl. In one embodiment, the optionally substituted aryl isan optionally substituted phenyl. In one embodiment, the optionallysubstituted phenyl has four substituents. In another embodiment, theoptionally substituted phenyl has three substituents. In anotherembodiment, the optionally substituted phenyl has two substituents. Inanother embodiment, the optionally substituted phenyl has onesubstituent. Non-limiting exemplary substituted aryl groups include2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl,2-bromophenyl, 2-cyanophenyl, 3-methylphenyl, 3-methoxyphenyl,3-fluorophenyl, 3-chlorophenyl, 3-cyanophenyl, 4-methylphenyl,4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl,4-cyanophenyl, 2,6-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl,3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-di-methoxyphenyl,3,5-di-fluorophenyl 3,5-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl,2-fluoro-3-chlorophenyl, 2-trifluoromethyl-4-cyanophenyl,2-fluoro-5-chlorophenyl, 2-fluoro-5-chlorophenyl,2-fluoro-4-chlorophenyl, 2-cyano-3-trifluorophenyl and3-chloro-4-fluorophenyl. The term optionally substituted aryl is meantto include groups having fused optionally substituted cycloalkyl andfused optionally substituted heterocyclo rings. Examples include:

For the purpose of the present disclosure, the term “aryloxy” as used byitself or as part of another group refers to an optionally substitutedaryl attached to a terminal oxygen atom. A non-limiting exemplaryaryloxy group is PhO—.

For the purpose of the present disclosure, the term “aralkyloxy” as usedby itself or as part of another group refers to an aralkyl groupattached to a terminal oxygen atom. A non-limiting exemplary aralkyloxygroup is PhCH₂O—.

For the purpose of the present disclosure, the term “heteroaryl” or“heteroaromatic” refers to monocyclic and bicyclic aromatic ring systemshaving 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms (i.e., C₅₋₁₄heteroaryl) and 1, 2, 3, or 4 heteroatoms independently chosen fromoxygen, nitrogen and sulfur. In one embodiment, the heteroaryl has threeheteroatoms. In another embodiment, the heteroaryl has two heteroatoms.In another embodiment, the heteroaryl has one heteroatom. In oneembodiment, the heteroaryl is a C₅ heteroaryl. In another embodiment,the heteroaryl is a C₆ heteroaryl. Non-limiting exemplary heteroarylgroups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl,thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl,benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl,pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl,3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl,phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl,4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl,pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl,phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl. In oneembodiment, the heteroaryl is chosen from thienyl (e.g., thien-2-yl andthien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g.,1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yland 2H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl,1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl,pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl,pyrimidin-4-yl, pyrimidin-5-yl, and pyrimidin-5-yl), thiazolyl (e.g.,thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g.,isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g.,oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl) and isoxazolyl (e.g.,isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl). The term “heteroaryl”is also meant to include possible N-oxides. Non-limiting exemplaryN-oxides include pyridyl N-oxide.

For the purpose of the present disclosure, the term “optionallysubstituted heteroaryl” as used by itself or as part of another groupmeans that the heteroaryl as defined above is either unsubstituted orsubstituted with 1, 2, 3, or 4 substituents, e.g., one or twosubstituents, independently chosen from halo, nitro, cyano, hydroxy,amino, alkylamino, dialkylamino, haloalkyl, monohydroxyalkyl,dihydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio,carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl,arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl,cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo,alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl,(dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl,(heterocyclo)alkyl, and (heteroaryl)alkyl. In one embodiment, theoptionally substituted heteroaryl has one substituent. In oneembodiment, the optionally substituted is an optionally substitutedpyridyl, i.e., 2-, 3-, or 4-pyridyl. Any available carbon or nitrogenatom can be substituted. In another embodiment, the optionallysubstituted heteroaryl is an optionally substituted indole.

For the purpose of the present disclosure, the term “heterocyclo” asused by itself or as part of another group refers to saturated andpartially unsaturated (e.g., containing one or two double bonds) cyclicgroups containing 1, 2, or 3 rings having from 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, or 14 carbon atoms (i.e., C₂₋₁₄ heterocyclo) and one ortwo oxygen, sulfur and/or nitrogen atoms. The term “heterocyclo” ismeant to include cyclic ureido groups such as 2-imidazolidinone andcyclic amide groups such as β-lactam, γ-lactam, δ-lactam and ε-lactam.The term “heterocyclo” is also meant to include groups having fusedoptionally substituted aryl groups, e.g., indolinyl. In one embodiment,the heterocyclo group is chosen from a 5- or 6-membered cyclic groupcontaining one ring and one or two oxygen and/or nitrogen atoms. Theheterocyclo can be optionally linked to the rest of the molecule througha carbon or nitrogen atom. In one embodiment the “heterocyclo” is a 3-to 8-membered heterocyclo. Non-limiting exemplary heterocyclo, i.e. 3-to 8-membered heterocyclo, groups include 2-imidazolidinone,piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and indolinyl.

For the purpose of the present disclosure, the term “optionallysubstituted heterocyclo” as used herein by itself or part of anothergroup means the heterocyclo as defined above is either unsubstituted orsubstituted with one to four substituents independently selected fromhalo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl,monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy, aryloxy,aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl,arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy,carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino,(alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and(heteroaryl)alkyl. Substitution may occur on any available carbon ornitrogen atom. Non-limiting exemplary optionally substituted heterocyclogroups include:

For the purpose of the present disclosure, the term “amino” as used byitself or as part of another group refers to —NH₂.

For the purpose of the present disclosure, the term “alkylamino” as usedby itself or as part of another group refers to —NHR¹³, wherein R¹³ isalkyl.

For the purpose of the present disclosure, the term “dialkylamino” asused by itself or as part of another group refers to —NR^(14a)R^(14b),wherein R^(14a) and R^(14b) are each independently alkyl or R^(14a) andR^(14b) are taken together to form a 3- to 8-membered optionallysubstituted heterocyclo.

For the purpose of the present disclosure, the term “hydroxyalkylamino”as used by itself or as part of another group refers to —NHR¹⁵, whereinR¹⁵ is monohydroxyalkyl or dihydroxyalkyl.

For the purpose of the present disclosure, the term “arylamino” as usedby itself or as part of another group refers to —NR^(16a)R^(16b),wherein R^(16a) is optionally substituted aryl and R^(16b) is hydrogenor alkyl.

For the purpose of the present disclosure, the term “cycloalkylamino” asused by itself or as part of another group refers to —NR^(17a)R^(17b),wherein R^(17a) is optionally substituted cycloalkyl and R^(17b) ishydrogen or alkyl.

For the purpose of the present disclosure, the term “heteroarylamino” asused by itself or as part of another group refers to —NR^(18a)R^(18b)wherein R^(18a) is optionally substituted heteroaryl and R^(18b) ishydrogen or alkyl.

For the purpose of the present disclosure, the term “heterocycloamino”as used by itself or as part of another group refers to —NR^(19a)R^(19b)wherein R^(19a) is optionally substituted heterocyclo and R^(19b) ishydrogen or alkyl.

For the purpose of the present disclosure, the term “(amino)alkyl” asused by itself or as part of another group refers to an alkyl groupsubstituted with an amino group. Non-limiting exemplary amino alkylgroups include —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, and —CH₂CH₂CH₂CH₂NH₂.

For the purpose of the present disclosure, the term “diaminoalkyl” asused by itself or as part of another group refers an alkyl groupsubstituted with two amino groups. A non-limiting exemplary diaminoalkylincludes —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, and —CH₂CH(NH₂)CH₂CH₂NH₂.

For the purpose of the present disclosure, the term “(alkylamino)alkyl”as used by itself or as part of another group refers to an alkyl groupsubstituted with an alkylamino group. A non-limiting exemplary(alkylamino)alkyl group is —CH₂CH₂N(H)CH₃.

For the purpose of the present disclosure, the term“(dialkylamino)alkyl” as used by itself or as part of another grouprefers to an alkyl group substituted by a dialkylamino group. Anon-limiting exemplary (dialkylamino)alkyl group is —CH₂CH₂N(CH₃)₂.

For the purpose of the present disclosure, the term “(cyano)alkyl” asused by itself or as part of another group refers to an alkyl groupsubstituted with one or more cyano, e.g., —CN, groups. Non-limitingexemplary (cyano)alkyl groups include —CH₂CH₂CN, —CH₂CH₂CH₂CN, and—CH₂CH₂CH₂CH₂CN.

For the purpose of the present disclosure, the term “carboxamido” asused by itself or as part of another group refers to a radical offormula —C(═O)NR^(20a)R^(20b) wherein R^(20a) and R^(20b) are eachindependently hydrogen, optionally substituted alkyl, optionallysubstituted aryl, or optionally substituted heteroaryl, or R^(20a) andR^(20b) taken together with the nitrogen atom to which they are attachedfrom a 3- to 8-membered heterocyclo group. In one embodiment, R^(20a)and R^(20b) are each independently hydrogen or optionally substitutedalkyl. Non-limiting exemplary carboxamido groups include —CONH₂,—CON(H)CH₃, CON(CH₃)₂, and CON(H)Ph.

For the purpose of the present disclosure, the term “(carboxamido)alkyl”as used by itself or as part of another group refers to an alkyl groupsubstituted with a carboxamido group. Non-limiting exemplary(carboxamido)alkyl groups include —CH₂CONH₂, —C(H)CH₃—CONH₂, and—CH₂CON(H)CH₃.

For the purpose of the present disclosure, the term “sulfonamido” asused by itself or as part of another group refers to a radical of theformula —SO₂NR^(21a)R^(21b) wherein R^(21a) and R^(21b) are eachindependently hydrogen, optionally substituted alkyl, or optionallysubstituted aryl, or R^(21a) and R^(21b) taken together with thenitrogen atom to which they are attached from a 3- to 8-memberedheterocyclo group. Non-limiting exemplary sulfonamido groups include—SO₂NH₂, —SO₂N(H)CH₃, and —SO₂N(H)Ph.

For the purpose of the present disclosure, the term “alkylcarbonyl” asused by itself or as part of another group refers to a carbonyl group,i.e., —C(═O)—, substituted by an alkyl group. A non-limiting exemplaryalkylcarbonyl group is —COCH₃.

For the purpose of the present disclosure, the term “arylcarbonyl” asused by itself or as part of another group refers to a carbonyl group,i.e., —C(═O)—, substituted by an optionally substituted aryl group. Anon-limiting exemplary arylcarbonyl group is —COPh.

For the purpose of the present disclosure, the term “alkylsulfonyl” asused by itself or as part of another group refers to a sulfonyl group,i.e., —SO₂—, substituted by any of the above-mentioned optionallysubstituted alkyl groups. A non-limiting exemplary alkylsulfonyl groupis —SO₂CH₃.

For the purpose of the present disclosure, the term “arylsulfonyl” asused by itself or as part of another group refers to a sulfonyl group,i.e., —SO₂—, substituted by any of the above-mentioned optionallysubstituted aryl groups. A non-limiting exemplary arylsulfonyl group is—SO₂Ph.

For the purpose of the present disclosure, the term “mercaptoalkyl” asused by itself or as part of another group refers to any of theabove-mentioned alkyl groups substituted by a —SH group.

For the purpose of the present disclosure, the term “carboxy” as used byitself or as part of another group refers to a radical of the formula—COOH.

For the purpose of the present disclosure, the term “halo” or “halogen”as used by itself or as part of another group refers to —F, —Cl, Br, or—I.

For the purpose of the present disclosure, the term “nitro” as used byitself or as part of another group refers to a radical of the formula—NO₂.

For the purpose of the present disclosure, the term “cyano” as used byitself or as part of another group refers to a radical of the formula—CN.

For the purpose of the present disclosure, the term “hydroxy” as used byitself or as part of another group refers to a radical of the formula—OH.

For the purpose of the present disclosure, the term “carboxyalkyl” asused by itself or as part of another group refers to any of theabove-mentioned alkyl groups substituted with a —COOH. Non-limitingexemplary carboxyalkyl groups include —CH₂CO₂H and —CH(CH₃)—CO₂H.

For the purpose of the present disclosure, the term “alkoxycarbonyl” asused by itself or as part of another group refers to a carbonyl group,i.e., —C(═O)—, substituted by an alkoxy group. Non-limiting exemplaryalkoxycarbonyl groups are —CO₂Me and —CO₂Et.

For the purpose of the present disclosure, the term“(alkoxycarbonyl)alkyl” as used by itself or as part of another grouprefers to an alkyl group substituted with an alkoxycarbonyl group.Non-limiting exemplary (alkoxycarbonyl)alkyl groups include —CH₂CO₂CH₃and —C(H)CH₃—CO₂CH₃.

For the purpose of the present disclosure, the term “aralkyl” as used byitself or as part of another group refers to an alkyl group substitutedwith one, two, or three optionally substituted aryl groups. In oneembodiment, the aralkyl group is a C₁₋₄ alkyl substituted with oneoptionally substituted aryl group. Non-limiting exemplary aralkyl groupsinclude benzyl, phenethyl, —CHPh₂, and —CH(4-F-Ph)₂.

For the purpose of the present disclosure, the term “ureido” as used byitself or as part of another group refers to a radical of the formula—NR^(22a)—C(═O)—NR^(22b)R^(22c), wherein R^(22a) is hydrogen, alkyl, oroptionally substituted aryl, and R^(22b) and R^(22c) are eachindependently hydrogen, alkyl, or optionally substituted aryl, orR^(22b) and R^(22c) taken together with the nitrogen to which they areattached form a 4- to 8-membered heterocyclo group. Non-limitingexemplary ureido groups include —NH—C(C═O)—NH₂ and —NH—C(C═O)—NHCH₃.

For the purpose of the present disclosure, the term “guanidino” as usedby itself or as part of another group refers to a radical of the formula—NR^(23a)—C(═NR²⁴)—NR^(23b)R^(23c), wherein R^(23a), R^(23b), andR^(23c) are each independently hydrogen, alkyl, or optionallysubstituted aryl, and R²⁴ is hydrogen, alkyl, cyano, alkylsulfonyl,alkylcarbonyl, carboxamido, or sulfonamido. Non-limiting exemplaryguanidino groups include —NH—C(C═NH)—NH₂, —NH—C(C═NCN)—NH₂,—NH—C(C═NH)—NHCH₃.

For the purpose of the present disclosure, the term “azido” as used byitself or as part of another group refers to a radical of the formula—N₃.

For the purpose of the present disclosure, the term “(heterocyclo)alkyl”as used by itself or as part of another group refers to an alkyl groupsubstituted with one, two, or three optionally substituted heterocyclogroups. In one embodiment, the (heterocyclo)alkyl is a C₁₋₄ alkylsubstituted with one optionally substituted heterocyclo group.Non-limiting exemplary (heterocyclo)alkyl groups include:

For the purpose of the present disclosure, the term “(heteroaryl)alkyl”as used by itself or as part of another group refers to an alkyl groupsubstituted with one, two, or three optionally substituted heteroarylgroups. In one embodiment, the (heteroaryl)alkyl group is a C₁₋₄ alkylsubstituted with one optionally substituted heteroaryl group.Non-limiting exemplary (heteroaryl)alkyl groups include:

For the purpose of the present disclosure, the term “alkylcarbonylamino”as used by itself or as part of another group refers to an alkylcarbonylgroup attached to an amino. A non-limiting exemplary alkylcarbonylaminogroup is —NHCOCH₃.

For the purpose of the present disclosure, the term “alkylcarbonyloxy”as used by itself or as part of another group refers to oxygensubstituted by one of the above-mentioned alkylcarbonyl groups. Anon-limiting exemplary alkylcarbonyloxy group is —OCOCH₃.

The present disclosure encompasses prodrugs of any of the disclosedcompounds. As used herein, prodrugs are considered to be any covalentlybonded carriers that release the active parent drug in vivo. In general,such prodrugs will be functional derivatives of Compounds of theInvention which will be readily convertible in vivo, e.g., by beingmetabolized, into the required Compound of the Invention. Conventionalprocedures for the selection and preparation of suitable prodrugderivatives are described in, for example, Design of Prodrugs, H.Bundgaard ed., Elsevier (1985); “Drug and Enzyme Targeting, Part A,” K.Widder et al. eds., Vol. 112 in Methods in Enzymology, Academic Press(1985); Bundgaard, “Design and Application of Prodrugs,” Chapter 5 (pp.113-191) in A Textbook of Drug Design and Development, P.Krogsgaard-Larsen and H. Bundgaard eds., Harwood Academic Publishers(1991); Bundgaard et al., Adv. Drug Delivery Revs. 8:1-38 (1992);Bundgaard et al., J. Pharmaceut. Sci. 77:285 (1988); and Kakeya et al.,Chem. Pharm. Bull. 32:692 (1984). Non-limiting examples of prodrugsinclude esters or amides of Compounds of the Invention havinghydroxyalkyl or aminoalkyl as a substituent, and these can be preparedby reacting such parent compounds with anhydrides such as succinicanhydride.

The present disclosure encompasses any of the Compounds of the Inventionbeing isotopically-labelled (i.e., radiolabeled) by having one or moreatoms replaced by an atom having a different atomic mass or mass number.Examples of isotopes that can be incorporated into the disclosedcompounds include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N,¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively, e.g., ³H, ¹¹C, and¹⁴C. Isotopically-labeled Compounds of the Invention can be prepared bymethods known in the art.

The present disclosure encompasses ³H, ¹¹C, or ¹⁴C radiolabeledCompounds of the Invention and the use of any such compounds asradioligands for their ability to bind to the sodium channel. Forexample, one use of the labeled compounds of the present disclosure isthe characterization of specific receptor binding. Another use of alabeled Compound of the Invention is an alternative to animal testingfor the evaluation of structure-activity relationships. For example, thereceptor assay can be performed at a fixed concentration of a labeledCompound of the Invention and at increasing concentrations of a testcompound in a competition assay. For example, a tritiated Compound ofthe Invention can be prepared by introducing tritium into the particularcompound, for example, by catalytic dehalogenation with tritium. Thismethod may include reacting a suitably halogen-substituted precursor ofthe compound with tritium gas in the presence of a suitable catalyst,for example, Pd/C, in the presence or absence of a base. Other suitablemethods for preparing tritiated compounds can be found in Filer,Isotopes in the Physical and Biomedical Sciences, Vol. 1, LabeledCompounds (Part A), Chapter 6 (1987). ¹⁴C-labeled compounds can beprepared by employing starting materials having a ¹⁴C carbon.

Some of the Compounds of the Invention may contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms. The present disclosure is meant toencompass the use of all such possible forms, as well as their racemicand resolved forms and mixtures thereof. The individual enantiomers canbe separated according to methods known in the art in view of thepresent disclosure. When the compounds described herein contain olefinicdouble bonds or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that they include both E and Zgeometric isomers. All tautomers are intended to be encompassed by thepresent disclosure as well.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The terms “enantiomer” and “enantiomeric” refer to a molecule thatcannot be superimposed on its mirror image and hence is optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image compound rotates the plane of polarizedlight in the opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich mixture is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

The terms “a” and “an” refer to one or more.

The term “treat,” “treating” or “treatment” is meant to encompassadministering to a subject a compound of the present disclosure for thepurposes of amelioration or cure, including preemptive and palliativetreatment.

The term “about,” as used herein in connection with a measured quantity,refers to the normal variations in that measured quantity, as expectedby the skilled artisan making the measurement and exercising a level ofcare commensurate with the objective of measurement and the precision ofthe measuring equipment.

The present disclosure encompasses the preparation and use of salts ofthe Compounds of the Invention, including non-toxic pharmaceuticallyacceptable salts. Examples of pharmaceutically acceptable addition saltsinclude inorganic and organic acid addition salts and basic salts. Thepharmaceutically acceptable salts include, but are not limited to, metalsalts such as sodium salt, potassium salt, cesium salt and the like;alkaline earth metals such as calcium salt, magnesium salt and the like;organic amine salts such as triethylamine salt, pyridine salt, picolinesalt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt,N,N′-dibenzylethylenediamine salt and the like; inorganic acid saltssuch as hydrochloride, hydrobromide, phosphate, sulphate and the like;organic acid salts such as citrate, lactate, tartrate, maleate,fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate,oxalate, formate and the like; sulfonates such as methanesulfonate,benzenesulfonate, p-toluenesulfonate and the like; and amino acid saltssuch as arginate, asparginate, glutamate and the like.

Acid addition salts can be formed by mixing a solution of the particularCompound of the Invention with a solution of a pharmaceuticallyacceptable non-toxic acid such as hydrochloric acid, fumaric acid,maleic acid, succinic acid, acetic acid, citric acid, tartaric acid,carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or thelike. Basic salts can be formed by mixing a solution of the compound ofthe present disclosure with a solution of a pharmaceutically acceptablenon-toxic base such as sodium hydroxide, potassium hydroxide, cholinehydroxide, sodium carbonate and the like.

The present disclosure encompasses the preparation and use of solvatesof Compounds of the Invention. Solvates typically do not significantlyalter the physiological activity or toxicity of the compounds, and assuch may function as pharmacological equivalents. The term “solvate” asused herein is a combination, physical association and/or solvation of acompound of the present disclosure with a solvent molecule such as, e.g.a disolvate, monosolvate or hemisolvate, where the ratio of solventmolecule to compound of the present disclosure is 2:1, 1:1 or 1:2,respectively. This physical association involves varying degrees ofionic and covalent bonding, including hydrogen bonding. In certaininstances, the solvate can be isolated, such as when one or more solventmolecules are incorporated into the crystal lattice of a crystallinesolid. Thus, “solvate” encompasses both solution-phase and isolatablesolvates. Compounds of the Invention can be present as solvated formswith a pharmaceutically acceptable solvent, such as water, methanol,ethanol, and the like, and it is intended that the disclosure includesboth solvated and unsolvated forms of Compounds of the Invention. Onetype of solvate is a hydrate. A “hydrate” relates to a particularsubgroup of solvates where the solvent molecule is water. Solvatestypically can function as pharmacological equivalents. Preparation ofsolvates is known in the art. See, for example, M. Caira et al, J.Pharmaceut. Sci., 93(3):601-611 (2004), which describes the preparationof solvates of fluconazole with ethyl acetate and with water. Similarpreparation of solvates, hemisolvates, hydrates, and the like aredescribed by E. C. van Tonder et al., AAPS Pharm. Sci. Tech.,5(1):Article 12 (2004), and A. L. Bingham et al., Chem. Commun. 603-604(2001). A typical, non-limiting, process of preparing a solvate wouldinvolve dissolving a Compound of the Invention in a desired solvent(organic, water, or a mixture thereof) at temperatures above 20° C. toabout 25° C., then cooling the solution at a rate sufficient to formcrystals, and isolating the crystals by known methods, e.g., filtration.Analytical techniques such as infrared spectroscopy can be used toconfirm the presence of the solvent in a crystal of the solvate.

Since Compounds of the Invention are blockers of sodium (Na⁺) channels,a number of diseases and conditions mediated by sodium ion influx can betreated by employing these compounds. The present disclosure is thusdirected generally to a method for treating a disorder responsive to theblockade of sodium channels in an animal suffering from, or at risk ofsuffering from, said disorder, said method comprising administering tothe animal an effective amount of one or more Compounds of theInvention.

The present disclosure is further directed to a method of modulatingsodium channels in an animal in need thereof, said method comprisingadministering to the animal a modulating-effective amount of at leastone Compound of the Invention.

More specifically, the present disclosure provides a method of treatingstroke, neuronal damage resulting from head trauma, epilepsy, neuronalloss following global and focal ischemia, pain (e.g., acute pain,chronic pain, which includes but is not limited to neuropathic pain,postoperative pain, and inflammatory pain, or surgical pain), aneurodegenerative disorder (e.g., Alzheimer's disease, amyotrophiclateral sclerosis (ALS), or Parkinson's disease), migraine, manicdepression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia. In one embodiment, thedisclosure provides a method of treating pain. In another embodiment,the type of pain is chronic pain. In another embodiment, the type ofpain is neuropathic pain. In another embodiment, the type of pain ispostoperative pain. In another embodiment, the type of pain isinflammatory pain. In another embodiment, the type of pain is surgicalpain. In another embodiment, the type of pain is acute pain. In anotherembodiment, the treatment of pain (e.g., chronic pain, such asneuropathic pain, postoperative pain, or inflammatory pain, acute painor surgical pain) is preemptive. In another embodiment, the treatment ofpain is palliative. In each instance, such method of treatment requiresadministering to an animal in need of such treatment an amount of aCompound of the Invention that is therapeutically effective in achievingsaid treatment. In one embodiment, the amount of such compound is theamount that is effective to block sodium channels in vitro. In oneembodiment, the amount of such compound is the amount that is effectiveto block sodium channels in vivo.

Chronic pain includes, but is not limited to, inflammatory pain,postoperative pain, cancer pain, osteoarthritis pain associated withmetastatic cancer, trigeminal neuralgia, acute herpetic and postherpeticneuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion,occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout,phantom limb pain, burn pain, and other forms of neuralgia, neuropathic,and idiopathic pain syndromes.

Chronic somatic pain generally results from inflammatory responses totissue injury such as nerve entrapment, surgical procedures, cancer orarthritis (Brower, Nature Biotechnology 18:387-391 (2000)).

The inflammatory process is a complex series of biochemical and cellularevents activated in response to tissue injury or the presence of foreignsubstances (Levine, Inflammatory Pain, In: Textbook of Pain, Wall andMelzack eds., 3^(rd) ed., 1994). Inflammation often occurs at the siteof injured tissue, or foreign material, and contributes to the processof tissue repair and healing. The cardinal signs of inflammation includeerythema (redness), heat, edema (swelling), pain and loss of function(ibid.). The majority of patients with inflammatory pain do notexperience pain continually, but rather experience enhanced pain whenthe inflamed site is moved or touched. Inflammatory pain includes, butis not limited to, that associated with osteoarthritis and rheumatoidarthritis.

Chronic neuropathic pain is a heterogeneous disease state with anunclear etiology. In chronic neuropathic pain, the pain can be mediatedby multiple mechanisms. This type of pain generally arises from injuryto the peripheral or central nervous tissue. The syndromes include painassociated with spinal cord injury, multiple sclerosis, post-herpeticneuralgia, trigeminal neuralgia, phantom pain, causalgia, and reflexsympathetic dystrophy and lower back pain. Chronic pain is differentfrom acute pain in that patients suffer the abnormal pain sensationsthat can be described as spontaneous pain, continuous superficialburning and/or deep aching pain. The pain can be evoked by heat-, cold-,and mechano-hyperalgesia or by heat-, cold-, or mechano-allodynia.

Neuropathic pain can be caused by injury or infection of peripheralsensory nerves. It includes, but is not limited to, pain from peripheralnerve trauma, herpes virus infection, diabetes mellitus, causalgia,plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathicpain is also caused by nerve damage from chronic alcoholism, humanimmunodeficiency virus infection, hypothyroidism, uremia, or vitamindeficiencies. Stroke (spinal or brain) and spinal cord injury can alsoinduce neuropathic pain. Cancer-related neuropathic pain results fromtumor growth compression of adjacent nerves, brain, or spinal cord. Inaddition, cancer treatments, including chemotherapy and radiationtherapy, can also cause nerve injury. Neuropathic pain includes but isnot limited to pain caused by nerve injury such as, for example, thepain from which diabetics suffer.

The present disclosure is also directed to the use of a Compound of theInvention in the manufacture of a medicament for treating a disorderresponsive to the blockade of sodium channels (e.g., any of thedisorders listed above) in an animal suffering from said disorder.

General Synthesis of Compounds

Compounds of the Invention can be prepared using methods known to thoseskilled in the art in view of this disclosure. For example, compoundshaving Formula I wherein R⁴ is 1,2-dihydroxyethyl can be preparedaccording to General Scheme 1.

Briefly, dichloropyrimide A is made to react with dioxaborolane B togive compound C. The carboxylic acid group of compound C is esterifiedto give compound D, and compound D is made to react with dioxaborolane Eto give compound F. The alkenyl group of compound F is dihydroxylated,for example using AD-Mix-α or AD-Mix-β, to give compound G (or the R- orS-isomer thereof). Compound G is made to react with amine HNR¹R² usingstandard coupling methods and reagents to give a compound having FormulaI wherein R⁴ is 1,2-dihydroxyethyl. One skilled in the art willrecognize that initially reacting dioxaborolane E with compound Ainstead of dioxaborolane B will provide a different pyrimidineregioisomer of Formula I.

Testing of Compounds

Representative Compounds of the Invention were assessed by sodiummobilization and/or electrophysiological assays for sodium channelblocker activity. One aspect of the present disclosure is based on theuse of the Compounds of the Invention as sodium channel blockers. Basedupon this property, Compounds of the Invention are considered useful intreating a condition or disorder responsive to the blockade of sodiumion channels, e.g., stroke, neuronal damage resulting from head trauma,epilepsy, seizures, general epilepsy with febrile seizures, severemyoclonic epilepsy in infancy, neuronal loss following global and focalischemia, migraine, familial primary erythromelalgia, paroxysmal extremepain disorder, cerebellar atrophy, ataxia, dystonia, tremor, mentalretardation, autism, a neurodegenerative disorder (e.g., Alzheimer'sdisease, amyotrophic lateral sclerosis (ALS), or Parkinson's disease),manic depression, tinnitus, myotonia, a movement disorder, cardiacarrhythmia, or providing local anesthesia. Compounds of the Inventionare also expected to be effective in treating pain, e.g., acute pain,chronic pain, which includes but is not limited to, neuropathic pain,postoperative pain, and inflammatory pain, or surgical pain.

More specifically, the present disclosure is directed to Compounds ofthe Invention that are blockers of sodium channels. According to thepresent disclosure, those compounds having useful sodium channelblocking properties exhibit an IC₅₀ for Na_(v)1.1, Na_(v)1.2, Na_(v)1.3,Na_(v)1.4, Na_(v)1.5, Na_(v)1.6, Na_(v)1.7, Na_(v)1.8, and/or Na_(y)1.9of about 100 μM or less, e.g., about 50 μM or less, about 25 μM or less,about 10 μM or less, about 5 μM or less, or about 1 μM or less, insodium mobilization and/or electrophysiological assays. In certainembodiments, Compounds of the Invention exhibit an IC₅₀ for Na_(v)1.7 of100 μM or less, about 50 μM or less, about 25 μM or less, about 10 μM orless, about 5 μM or less, about 1 μM or less, about 0.5 μM or less,about 0.1 μM or less, about 0.05 μM or less, or about 0.01 μM or less.Compounds of the Invention can be tested for their Na⁺ channel blockingactivity using methods known in the art and by the followingfluorescence imaging and electrophysiological in vitro assays and/or invivo assays.

In one embodiment, Compounds of the Invention demonstrate substantiallyno penetration across the CNS blood-brain barrier in a mammal. Suchcompounds are referred to as “peripherally restricted” as a means todesignate their PNS versus CNS tissue selectivity.

In one embodiment, the PNS:CNS concentration ratio of a peripherallyrestricted Compound of the Invention is about 5:1, about 10:1, about20:1, about 30:1; about 50:1; about 100:1, about 250:1, about 500:1,about 1000:1, about 5,000:1, about 10,000:1, or more. Compounds of theInvention can be tested for their ability to penetrate the centralnervous system using in vitro and in vivo methods known in the art.

In Vitro Assay Protocols

FLIPR® Assays

Recombinant Na_(v)1.7 Cell Line: In vitro assays were performed in arecombinant cell line expressing cDNA encoding the alpha subunit(Na_(v)1.7, SCN9a, PN1, NE) of human Na_(v)1.7 (AccessionNo._NM_002977). The cell line was provided by investigators at YaleUniversity (Cummins et al, J. Neurosci. 18(23): 9607-9619 (1998)). Fordominant selection of the Na_(v)1.7-expressing clones, the expressionplasmid co-expressed the neomycin resistance gene. The cell line wasconstructed in the human embryonic kidney cell line, HEK293, under theinfluence of the CMV major late promoter, and stable clones wereselected using limiting dilution cloning and antibiotic selection usingthe neomycin analogue, G418. Recombinant beta and gamma subunits werenot introduced into this cell line. Additional cell lines expressingrecombinant Na_(v)1.7 cloned from other species can also be used, aloneor in combination with various beta subunits, gamma subunits orchaperones.

Non-recombinant Cell Lines Expressing Native Na_(v)1.7: Alternatively,in vitro assays can be performed in a cell line expressing native,non-recombinant Na_(v)1.7, such as the ND7 mouse neuroblastoma X ratdorsal root ganglion (DRG) hybrid cell line ND7/23, available from theEuropean Cell Culture Collection (Cat. No. 92090903, Salisbury,Wiltshire, United Kingdom). The assays can also be performed in othercell lines expressing native, non-recombinant Na_(v)1.7, from variousspecies, or in cultures of fresh or preserved sensory neurons, such asdorsal root ganglion (DRG) cells, isolated from various species. Primaryscreens or counter-screens of other voltage-gated sodium channels canalso be performed, and the cell lines can be constructed using methodsknown in the art, purchased from collaborators or commercialestablishments, and they can express either recombinant or nativechannels. The primary counter-screen is for one of the central neuronalsodium channels, Na_(V)1.2 (rBIIa), expressed in HEK293 host cells(Ilyin et al., Br. J. Pharmacol. 144:801-812 (2005)). Pharmacologicalprofiling for these counter-screens is carried out under conditionssimilar to the primary or alternative Na_(v)1.7 assays described below.

Cell maintenance: Unless otherwise noted, cell culture reagents werepurchased from Mediatech of Herndon, Va. The recombinantNa_(v)1.7/HEK293 cells were routinely cultured in growth mediumconsisting of Dulbecco's minimum essential medium containing 10% fetalbovine serum (FBS, Hyclone, Thermo Fisher Scientific, Logan, Utah), 100U/mL penicillin, 100 μg/mL streptomycin, 2-4 mM L-glutamine, and 500mg/mL G418. For natural, non-recombinant cell lines, the selectiveantibiotic was omitted, and additional media formulations can be appliedas needed.

Assay Buffer: The assay buffer was formulated by removing 120 mL from a1 L bottle of fresh, sterile dH₂O (Mediatech, Herndon, Va.) and adding100 mL of 10×HBSS that does not contain Ca⁺⁺ or Mg⁺⁺ (Gibco, Invitrogen,Grand Island, N.Y.) followed by 20 mL of 1.0 M Hepes, pH 7.3 (FisherScientific, BP299-100). The final buffer consisted of 20 mM Hepes, pH7.3, 1.261 mM CaCl₂, 0.493 mM MgCl₂, 0.407 mM Mg(SO)₄, 5.33 mM KCl,0.441 mM KH₂PO₄, 137 mM NaCl, 0.336 mM Na₂HPO₄ and 0.556 mM D-glucose(Hanks et al., Proc. Soc. Exp. Biol. Med. 71:196 (1949)), and the simpleformulation was typically the basic buffer throughout the assay (i.e.,all wash and addition steps).

CoroNa™ Green AM Na⁻ Dye for Primary Fluorescence Assay: Thefluorescence indicator used in the primary fluorescence assay was thecell permeant version of CoroNa™ Green (Invitrogen, Molecular Probes,Eugene, Oreg.), a dye that emits light in the fluorescence range(Harootunian et al., J. Biol, Chem. 264(32):19458-19467 (1989)). Theintensity of this emission, but not the wavelength range, is increasedwhen the dye is exposed to Na⁺ ions, which it can bind with partialselectivity. Cells expressing Na_(v)1.7 or other sodium channels wereloaded with the CoroNa™ Green dye immediately in advance of thefluorescence assay, and then, after agonist stimulation, themobilization of Na⁺ ions was detected as the Na⁺ ions flowed from theextracellular fluid into the cytoplasm through the activated sodiumchannel pores. The dye was stored in the dark as a lyophilized powder,and then an aliquot was dissolved immediately before the cell loadingprocedure, according to the instructions of the manufacturer to a stockconcentration of 10 mM in DMSO. It was then diluted in the assay bufferto a 4× concentrated working solution, so that the final concentrationof dye in the cell loading buffer was 5 μM.

Membrane Potential Dye for Alternative Fluorescence Assays: Afluorescence indicator that can be used in alternative fluorescenceassays is the blue version membrane potential dye (MDS, MolecularDevices, Sunnyvale, Calif.), a dye that detects changes in moleculesfollowing a change in membrane potential. An increase in fluorescence isexpected if agonist stimulation provokes a change in membrane potential.Cells expressing Na_(v)1.7 or other sodium channels are incubated withthe membrane potential dye 30-60 minutes before the fluorescence assay.In the case of the KCl pre-stimulation version of the assay, the dye andall other components are washed out immediately before the assay, andthe dye is then replaced. In the version lacking KCl pre-stimulation,the dye remains on the cells and is not washed out or replaced. The dyeis stored in the dark as a lyophilized powder, and then an aliquotdissolved in assay buffer to form a 20×-concentrated stock solution thatcan be used for several weeks.

Agonists: In the fluorescence assays, two agonists were used incombination, namely 1) veratridine; and 2) the venom from the yellowscorpion, Leiurus quinquestriatus hebraeus. Veratridine is an alkaloidsmall molecule that facilitates the capture of channel openings byinhibiting inactivation, and the scorpion venom is a natural preparationthat includes peptide toxins selective for different subsets ofvoltage-gated sodium channels. These scorpion toxins inhibit the fastinactivation of their cognate target channels. Stock solutions of theagonists were prepared to 40 mM in DMSO (veratridine) and 1 mg/mL indH₂O (scorpion venom), and then diluted to make a 4× or 2× stock(depending on the particular assay) in assay buffer, the finalconcentration being 100 μM (veratridine) and 10 μg/mL (scorpion venom).Both of the agonists were purchased from Sigma Aldrich, St. Louis, Mo.

Test Compounds: Test compounds were dissolved in DMSO to yield 10 mMstock solutions. The stock solutions were further diluted using DMSO in1:3 serial dilution steps with 10 points (10,000 μM, 3.333 μM, 1.111 μM,370 μM, 123 μM, 41 μM, 14 μM, 4.6 μM, 1.5 μM and 0.5 μM). The stocksolutions were further diluted in assay buffer (1:125) as 4× stockserial dilutions with a DMSO concentration of 0.8% (final [DMSO], in theassay, from the compounds component=0.2%), so that the compounds' finalconcentrations in the assay were 20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μMand 0.08 μM, 0.03 μM, 0.01 μM, 0.003 μM and 0.001 μM. If a particulartest article appeared to be especially potent, then the concentrationcurve was adjusted, e.g., to 10-fold lower concentrations, in order toperform the dose-response in a more relevant concentration range.Compound dilutions were added during the dye-loading and pre-stimulationstep, and then again during the fluorescence assay, early in the kineticread. Compound dilutions were added in duplicate rows across the middle80 wells of the 96-well plate, whereas the fully stimulated and thefully inhibited controls (positive and negative) were located in the top4 side wells and the bottom 4 side wells, respectively, on the left andright sides of the assay plate.

Data Analysis: The data were analyzed according to methods known tothose skilled in the art or using the GraphPad® Prism version 4.0 orhigher, Program (available from GraphPad Software, San Diego, Calif.) todetermine the IC₅₀ value for the test article. At least one standardreference compound was evaluated during each experiment.

FLIPR® or FLIPR^(TETA)® sodium dye assay with KCl and test articlepre-incubation: Cells were prepared by plating the recombinant HEK293cells or other host cells expressing either recombinant ornon-recombinant, native, Na_(V)1.7 alpha subunit, alone or incombination with various beta and gamma subunits at a density of ˜40,000cells/well into a 96-well black, clear-bottom, PDL-coated plate. Theassay can be adapted to 384-well or 1,536-well format, if desired, usingproportionately less cells and media. The plate was then incubated ingrowth media, with or without selective antibiotic, overnight at 37° C.at 5% CO₂, 95% humidity, in preparation for the assay. Forcounter-screens of other voltage-gated sodium channels, the procedurewas very similar, though optimal densities of cells, media andsubsequent assay components can be fine-tuned for the particular cellline or isoform.

The next day, at the start of the assay, the media was flicked from thecells and the wells were washed once with 50 μl/well assay buffer (1×Hank's balanced salt solution without sodium bicarbonate or phenol red,20 mM Hepes, pH 7.3) and then pre-incubated with the test articles,CoroNa™ Green AM sodium dye (for cell loading) and KCl forre-polarization and synchronization of the channels in the entirepopulation of cells. For this dye-loading and pre-stimulation step, thecomponents were added as follows, immediately after the wash step: 1)first, the compound dilutions and controls were added as 4× concentratesin assay buffer at 50 μL/well; 2) CoroNa™ Green AM dye was diluted fromthe stock solution to 20 μM in assay buffer (4× concentrate) and addedto the plate at 50 μL/well; and 3) finally, a solution of 180 mM KCl(2×) was prepared by diluting a 2M stock solution into assay buffer andthe solution was added to the cells at 100 μl/well. The cells wereincubated at 25° C. in the dark for 30 min. before their fluorescencewas measured.

The plates containing dye-loaded cells were then flicked to remove thepre-incubation components and washed once with 100 μL/well assay buffer.A 100 μL/well aliquot of assay buffer was added back to the plate, andthe real-time assay was commenced. The fluorescence of cells wasmeasured using a fluorescence plate reader (FLIPR^(TETRA)® or FLIPR384®,MDS, Molecular Devices, Sunnyvale, Calif.) Samples were excited byeither a laser or a PMT light source (Excitation wavelength=470-495 nM)and the emissions were filtered (Emission wavelength=515-575 nM). Theadditions of compound and the channel activators in this cell-based,medium-to-high throughput assay were performed on the fluorescence platereader and the results (expressed as relative fluorescence units) werecaptured by means of camera shots every 1-3 sec., then displayed inreal-time and stored. Generally, there was a 15 sec. base line, withcamera shots taken every 1.5 sec., then the test compounds were added,then another 120 sec. baseline was conducted, with camera shots takenevery 3 sec.; and finally, the agonist solution (containing veratridineand scorpion venom) was added. The amplitude of fluorescence increase,resulting from the binding of Na⁺ ions to the CoroNa™ Green dye, wascaptured for ˜180 sec. thereafter. Results were expressed in relativefluorescence units (RFU) and can be determined by using the maximumsignal during the latter part of the stimulation; or the maximum minusthe minimum during the whole agonist stimulation period; or by takingthe area under the curve for the whole stimulation period.

The assay was performed as a screening assay as well with the testarticles present in standard amounts (e.g., 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen were typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gate sodium channels or other biologicallyrelevant target molecules.

FLIPR® or FLIPR^(TETRA)® membrane potential assay with KCl and testarticle pre-incubation: Cells are prepared by plating the recombinantHEK293 cells or other host cells expressing either recombinant ornon-recombinant, native, Na_(v)1.7 alpha subunit, alone or incombination with various beta and gamma subunits at a density of ˜40,000cells/well into a 96-well black, clear-bottom, PDL-coated plate. Theassay can be adapted to 384-well or 1,536-well format, if desired, usingproportionately less cells and media. The plate is then incubated ingrowth media, with or without selective antibiotic, overnight at 37° C.at 5% CO₂, 95% humidity, in preparation for the assay (see, e.g.,Benjamin et. al., J. Biomol. Screen 10(4):365-373 (2005)). For screensand counter-screens of other voltage-gated sodium channels, the assayprotocol is similar, though optimal densities of cells, media andsubsequent assay components can be fine-tuned for the particular cellline or sodium channel isoform being tested.

The next day, at the start of the assay, the media is flicked from thecells and the wells are washed once with 50 μL/well assay buffer (1×Hank's balanced salt solution without sodium bicarbonate or phenol red,20 mM Hepes, pH 7.3) and then pre-incubated with the test articles, themembrane potential dye (for cell loading), and the KCl forre-polarization and synchronization of the channels in the entirepopulation of cells. For this dye-loading and pre-stimulation step, thecomponents are added as follows, immediately after the wash step: 1)first, the compound dilutions and controls are added as 4× concentratesin assay buffer at 50 L/well; 2) membrane potential dye is diluted fromthe stock solution in assay buffer (4× concentrate) and added to theplate at 50 μL/well; and 3) finally, a solution of 180 mM KCl (2×) isprepared by diluting a 2M stock solution into assay buffer and thesolution added to the cells at 100 L/well. The cells are incubated at37° C. in the dark for 30-60 min. before their fluorescence is measured.

The plates containing dye-loaded cells are then flicked to remove thepre-incubation components and washed once with 50 L/well assay buffer. A50 μL/well aliquot of membrane potential dye is added back to the plate,and the real-time assay is commenced. The fluorescence of cells ismeasured using a fluorescence plate reader (FLIPR^(TETRA)® Or FLIPR384®,MDS, Molecular Devices, Sunnyvale, Calif.). Samples are excited byeither a laser or a PMT light source (Excitation wavelength=510-545 nM)and the emissions are filtered (Emission wavelength=565-625 nM). Theadditions of the compounds (first) and then the channel activators(later) in this are performed on the fluorescence plate reader and theresults, expressed as relative fluorescence units (RFU), are captured bymeans of camera shots every 1-3 sec., then displayed in real-time andstored. Generally, there is a 15 sec. base line, with camera shots takenevery 1.5 sec., then the test compounds are added, then another 120 sec.baseline is conducted, with camera shots taken every 3 sec.; andfinally, the agonist solution (containing veratridine and scorpionvenom) is added. The amplitude of fluorescence increase, resulting fromthe detection of membrane potential change, is captured for ˜120 sec.thereafter. Results are expressed in relative fluorescence units (RFU)and can be determined by using the maximum signal during the latter partof the stimulation; or the maximum minus the minimum during the wholestimulation period; or by taking the area under the curve for the wholestimulation period.

The assay can be performed as a screening assay as well with the testarticles present in standard amounts (e.g., 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen are typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gate sodium channels or other biologicallyrelevant target molecules.

FLIPR® or FLIPR^(TETRA)® sodium dye assay without KCl and test articlepre-incubation: Cells are prepared by plating the recombinant HEK293cells or other host cells expressing either recombinant ornon-recombinant, native, Na_(V)1.7 alpha subunit, alone or incombination with various beta and gamma subunits at a density of ˜40,000cells/well into a 96-well black, clear-bottom, PDL-coated plate. Theassay can be adapted to 384-well or 1,536-well format, if desired, usingproportionately less cells and media. The plate is then incubated ingrowth media, with or without selective antibiotic, overnight at 37° C.at 5% CO₂, 95% humidity, in preparation for the assay. Forcounter-screens of other voltage-gated sodium channels, the procedure isvery similar, though optimal densities of cells, media and subsequentassay components can be fine-tuned for the particular cell line orisoform.

The next day, at the start of the assay, the media is flicked from thecells and the wells washed once with 50 μL/well assay buffer (1× Hank'sbalanced salt solution without sodium bicarbonate or phenol red, 20 mMHepes, pH 7.3). Membrane potential dye is then added to each well of the96-well plate (50 μL/well), from a freshly diluted sample of the stock(now at 4× concentration) in the assay buffer. The cells are incubatedat 37° C. in the dark for 30-60 min. before their fluorescence ismeasured.

In this standard membrane potential assay, the 96-well plate containingdye-loaded cells is then loaded directly onto the plate reader withoutaspirating the dye solution and without any further washing of thecells. The fluorescence of cells is measured using a fluorescence platereader (FLIPR^(TETRA)® or FLIPR384®, MDS, Molecular Devices, Sunnyvale,Calif.). Samples are excited by either a laser or a PMT light source(Excitation wavelength=510-545 nM) and the emissions are filtered(Emission wavelength=565-625 nM). The additions of the compounds (first,50 μL/well from a 4× stock plate) and then the channel activators(later, 100 μL/well from a 2× stock solution) in this kinetic assay areperformed on the fluorescence plate reader and the results, expressed asrelative fluorescence units (RFU), are captured by means of camera shotsevery 1-3 sec., then displayed in real-time and stored. Generally, thereis a 15 sec. base line, with camera shots taken every 1.5 sec., then thetest compounds are added, then another 120 sec. baseline is conducted,with camera shots taken every 3 sec.; and finally, the agonist solution(containing veratridine and scorpion venom) is added. The amplitude offluorescence increase, resulting from the detection of membranepotential change, is captured for ˜120 sec. thereafter. Results areexpressed in relative fluorescence units (RFU) and can be determined byusing the maximum signal during the latter part of the stimulation; orthe maximum minus the minimum during the whole stimulation period; or bytaking the area under the curve for the whole stimulation period.

The assay can be performed as a screening assay as well, with the testarticles present in standard amounts (e.g. 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen are typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gate sodium channels or other biologicallyrelevant target molecules.

Electrophysiology Assay Cells: The hNa_(v)1.7 expressing HEK-293 cellswere plated on 35 mm culture dishes pre-coated with poly-D-lysine instandard DMEM culture media (Mediatech, Inc., Herndon, Va.) andincubated in a 5% CO₂ incubator at 37° C. Cultured cells were usedapproximately 12-48 hours after plating.

Electrophysiology: On the day of experimentation, the 35 mm dish wasplaced on the stage of an inverted microscope equipped with a perfusionsystem that continuously perfuses the culture dish with fresh recordingmedia. A gravity driven superfusion system was used to apply testsolutions directly to the cell under evaluation. This system consists ofan array of glass pipette glass connected to a motorized horizontaltranslator. The outlet of the shooter was positioned approximately 100μm from the cell of interest.

Whole cell currents were recorded using the whole-cell patch clampconfiguration using an Axopatch 200B amplifier (Axon Instruments, FosterCity Calif.), 1322A A/D converter (Axon Instruments) and pClamp software(v. 8; Axon Instruments) and stored on a personal computer. Gigasealswere formed and the whole-cell configuration was established in voltageclamp mode, and membrane currents generated by hNa_(v)1.7 were recordedin gap-free mode. Borosilicate glass pipettes have resistance valuesbetween 1.5 and 2.0 MS when filled with pipette solution and seriesresistance (<5 MΩ) was compensated 75-80%. Signals were sampled at 50kHz and low pass filtered at 3 kHz.

Voltage protocols: After establishing the whole-cell configuration involtage clamp mode, voltage protocols were run to establish the 1) testpotential, 2) holding potential, and 3) the conditioning potential foreach cell.

After establishing the whole-cell configuration in voltage clamp mode, astandard I-V protocol was run to determine the potential at which themaximal current (I_(max)) is elicited. This potential was the testpotential (V_(t)). To determine a conditioning potential at which 100%of channels were in the inactivated state, a standard steady-stateinactivation (SSIN) protocol was run using a series of fifteen 100ms-long depolarizing prepulses, incrementing in 10 mV steps, immediatelyfollowed by a 5 ms testing pulse, V_(t), to V_(max). This protocol alsopermitted determination of the holding potential at which all channelsare in the resting state.

For compounds causing significant retardation of recovery frominactivation, an estimate of the affinity for the inactivated state ofthe channel (K_(t)) was generated using the following protocol. From thenegative, no residual inactivation, holding potential, the cell wasdepolarized to the conditioning voltage for 2-5 seconds, returned to thenegative holding potential for 10-20 ms to relieve fast inactivation andthen depolarized to the test potential for ˜15 ms. This voltage protocolwas repeated every 10-15 seconds, first to establish a baseline in theabsence of the test compound, then in the presence of the test compound.

After a stable baseline was established, the test compound was appliedand block of the current elicited by the test pulse assessed. In somecases, multiple cumulative concentrations were applied to identify aconcentration that blocked between 40-60% of this current. Washout ofthe compound was attempted by superfusing with control solution oncesteady-state block was observed. An estimate of the K_(i) was calculatedas follows:K _(i)=[drug]*{FR/(1−FR)},  Eq. 1

where [drug] is the concentration of a drug, andFR=I(after drug)/I(control),  Eq. 2where I is the peak current amplitude. If multiple concentrations wereused, K_(i), was determined from the fit of a logistic equation to FRsplotted against corresponding drug concentrations.

In the alternative, the voltage clamp protocol to examine hNa_(v)1.7currents was as follows. First, the standard current-voltagerelationship was tested by pulsing the cell from the holding voltage(V_(h)) of −120 mV by a series of 5 msec long square-shaped test pulsesincrementing in +10 mV steps over the membrane voltage range of −90 mVto +60 mV at the pace of stimulation of 0.5 Hz. This proceduredetermines the voltage that elicits the maximal current (V_(max)).Second, V_(h) was re-set to −120 mV and a steady-state inactivation(SSIN) curve was taken by the standard double-pulse protocol: 100 msdepolarizing pre-pulse was incremented in steps of +10 mV (voltage rangefrom −90 mV to 0 mV) immediately followed by the 5 ms long test pulse to−10 mV at the pace of stimulation of 0.2 Hz. This procedure determinesthe voltage of full inactivation (V_(full)). Third, the cell wasrepeatedly stimulated with the following protocol, first in the absenceof the test compound then in its presence. The protocol consisted ofdepolarizing the cell from the holding potential of −120 mV to theV_(full) value for 4.5 seconds then repolarizing the cell to the holdingpotential for 10 ms before applying the test pulse to the V_(max) for 5ms. The amount of inhibition produced by the test compound wasdetermined by comparing the current amplitude elicited by the test pulsein the absence and presence of the compound.

In a further alternative, the voltage clamp protocol to examinehNa_(v)1.7 currents was as follows. After establishing the whole-cellconfiguration in voltage clamp mode, two voltage protocols were run toestablish: 1) the holding potential; and 2) the test potential for eachcell.

Resting block: To determine a membrane potential at which the majorityof channels are in the resting state, a standard steady-stateinactivation (SSIN) protocol was run using 100 ms prepulses×10 mVdepolarizing steps. The holding potential for testing resting block(Vh₁) was 20 mV more hyperpolarized than the first potential whereinactivation was observed with the inactivation protocol.

From this holding potential a standard I-V protocol was run to determinethe potential at which the maximal current (Imax) is elicited. Thispotential was the test potential (Vt).

The compound testing protocol was a series of 10 ms depolarizations fromthe Vh₁ (determined from the SSIN) to the Vt (determined from the I-Vprotocol) repeated every 10-15 seconds. After a stable baseline wasestablished, a high concentration of a test compound (highestconcentration solubility permits or that which provides ˜50% block) wasapplied and block of the current assessed. Washout of the compound wasattempted by superfusing with control solution once steady-state blockwas observed. The fractional response was calculated as follows:K _(r)=[drug]*{FR/(1−FR)},  Eq. 3where [drug] is the concentration of a drug, andFR=I(after drug)/I(control),  Eq. 2where I is the peak current amplitude and was used for estimatingresting block dissociation constant, K_(r).

Block of inactivated channels: To assess the block of inactivatedchannels the holding potential was depolarized such that 20-50% of thecurrent amplitude was reduced when pulsed to the same Vt as above. Themagnitude of this depolarization depends upon the initial currentamplitude and the rate of current loss due to slow inactivation. Thiswas the second holding potential (Vh₂). The current reduction wasrecorded to determine the fraction of available channels at thispotential (h).h=I @Vh ₂ /Imax.  Eq. 4

At this membrane voltage a proportion of channels was in the inactivatedstate, and thus inhibition by a blocker includes interaction with bothresting and inactivated channels.

To determine the potency of the test compound on inactivated channels, aseries of currents were elicited by 10 ms voltage steps from Vh₂ toV_(t) every 10-15 seconds. After establishing a stable baseline, the lowconcentration of the compound was applied. In some cases, multiplecumulative concentrations will have to be applied to identify aconcentration that blocks between 40-60% of the current. Washout isattempted to re-establish baseline. Fractional responses were measuredwith respect to a projected baseline to determine K_(app).K _(app)=[drug]*{FR/(1−FR)},  Eq. 5where [drug] is the concentration of a drug.

This K_(app) value, along with the calculated K_(r) and h values, wereused to calculate the affinity of the compound for the inactivatedchannels (K_(i)) using the following equation:K _(i)=(1−h)/((1/K _(app))−(h/K _(r))).  Eq. 6

Solutions and chemicals: For electrophysiological recordings theexternal solution was either standard, DMEM supplemented with 10 mMHEPES (pH adjusted to 7.34 with NaOH and the osmolarity adjusted to 320)or Tyrodes salt solution (Sigma, USA) supplemented with 10 mM HEPES (pHadjusted to 7.4 with NaOH; osmolarity=320). The internal pipettesolution contained (in mM): NaCl (10), CsF (140), CaCl₂ (1), MgCl₂ (5),EGTA (11), HEPES (10: pH 7.4, 305 mOsm). Compounds were prepared firstas series of stock solutions in DMSO and then dissolved in externalsolution; DMSO content in final dilutions did not exceed 0.3%. At thisconcentration, DMSO did not affect sodium currents. Vehicle solutionused to establish base line was also contacting 0.3% DMSO.

Data analysis: Data was analyzed off-line using Clampfit software(pClamp, v. 8; Axon Instruments) and graphed using GraphPad Prism (v.4.0 or higher) software.

In Vivo Assay for Pain

Compounds of the Invention can be tested for their antinociceptiveactivity in the formalin model as described in Hunskaar et al., J.Neurosci. Methods 14: 69-76 (1985). Male Swiss Webster NIH mice (20-30g; Harlan, San Diego, Calif.) can be used in all experiments. Food iswithdrawn on the day of experiment. Mice are placed in Plexiglass jarsfor at least 1 hour to acclimate to the environment. Following theacclimation period, mice are weighed and given either the compound ofinterest administered i.p. or p.o., or the appropriate volume of vehicle(for example, 10% Tween-80 or 0.9% saline, and other pharmaceuticallyacceptable vehicles) as control. Fifteen minutes after the i.p. dosing,and 30 minutes after the p.o. dosing mice are injected with formalin (20μL of 5% formaldehyde solution in saline) into the dorsal surface of theright hind paw. Mice are transferred to the Plexiglass jars andmonitored for the amount of time spent licking or biting the injectedpaw. Periods of licking and biting are recorded in 5-minute intervalsfor 1 hour after the formalin injection. All experiments are done in ablinded manner during the light cycle. The early phase of the formalinresponse is measured as licking/biting between 0-5 minutes, and the latephase is measured from 15-50 minutes. Differences between vehicle anddrug treated groups can be analyzed by one-way analysis of variance(ANOVA). A P value <0.05 is considered significant. Compounds areconsidered to be efficacious for treating acute and chronic pain if theyhave activity in blocking both the early and second phase offormalin-induced paw-licking activity.

In Vivo Assays for Inflammatory or Neuropathic Pain

Test Animals:

Each experiment uses rats weighing between 200-260 g at the start of theexperiment. The rats are group-housed and have free access to food andwater at all times, except prior to oral administration of a testcompound when food is removed for 16 h before dosing. A control groupacts as a comparison to rats treated with a Compound of the Invention.The control group is administered the carrier as used for the testcompound. The volume of carrier administered to the control group is thesame as the volume of carrier and test compound administered to the testgroup.

Inflammatory Pain:

To assess the actions of Compounds of the Invention on the treatment ofinflammatory pain the Freund's complete adjuvant (“FCA”) model ofinflammatory pain is used. FCA-induced inflammation of the rat hind pawis associated with the development of persistent inflammatory mechanicaland thermal hyperalgesia and provides reliable prediction of theanti-hyperalgesic action of clinically useful analgesic drugs (Bartho etal., Naunyn-Schmiedeberg's Archives of Pharmacol. 342:666-670 (1990)).The left hind paw of each animal is administered a 50 μL intraplantarinjection of 50% FCA. 24 hour post injection, the animal is assessed forresponse to noxious mechanical stimuli by determining the paw withdrawalthreshold (PWT), or to noxious thermal stimuli by determining the pawwithdrawal latency (PWL), as described below. Rats are then administereda single injection of either a test compound or 30 mg/Kg of a positivecontrol compound (indomethacin)), or an equal volume of vehicle as anegative control. Responses to noxious mechanical or thermal stimuli arethen determined 1, 3, 5 and 24 hours post administration (admin).Percentage reversal of hyperalgesia for each animal is defined as:

${\%\mspace{14mu}{reversal}} = {\frac{\begin{matrix}\left\lbrack {\left( {{post}\mspace{14mu}{administration}{\mspace{11mu}\;}{PWT}\mspace{14mu}{or}\mspace{20mu}{PWL}} \right) -} \right. \\\left. \left( {{pre}\text{-}{administration}\mspace{14mu}{PWT}\mspace{14mu}{or}\mspace{14mu}{PWL}} \right) \right\rbrack\end{matrix}}{\begin{matrix}\left\lbrack {\left( {{baseline}\mspace{14mu}{PWT}\mspace{14mu}{or}\mspace{14mu}{PWL}} \right) -} \right. \\\left. \left( {{pre}\text{-}{administration}\mspace{14mu}{PWT}{\mspace{11mu}\;}{or}\mspace{14mu}{PWL}} \right) \right\rbrack\end{matrix}} \times 100}$

Neuropathic Pain:

To assess the actions of the test compounds for the treatment ofneuropathic pain the Seltzer model or the Chung model can be used.

In the Seltzer model, the partial sciatic nerve ligation model ofneuropathic pain is used to produce neuropathic hyperalgesia in rats(Seltzer et al., Pain 43:205-218 (1990)). Partial ligation of the leftsciatic nerve is performed under isoflurane/O₂ inhalation anesthesia.Following induction of anesthesia, the left thigh of the rat is shavedand the sciatic nerve exposed at high thigh level through a smallincision and is carefully cleared of surrounding connective tissues at asite near the trocanther just distal to the point at which the posteriorbiceps semitendinosus nerve branches off of the common sciatic nerve. A7-0 silk suture is inserted into the nerve with a ⅜ curved,reversed-cutting mini-needle and tightly ligated so that the dorsal ⅓ to½ of the nerve thickness is held within the ligature. The wound isclosed with a single muscle suture (4-0 nylon (Vicryl)) and vetbondtissue glue. Following surgery, the wound area is dusted with antibioticpowder. Sham-treated rats undergo an identical surgical procedure exceptthat the sciatic nerve is not manipulated. Following surgery, animalsare weighed and placed on a warm pad until they recover from anesthesia.Animals are then returned to their home cages until behavioral testingbegins. The animals are assessed for response to noxious mechanicalstimuli by determining PWT, as described below, prior to surgery(baseline), then immediately prior to and 1, 3, and 5 hours after drugadministration for the ipsilateral (same side as the injury) rear paw ofthe animal. Percentage reversal of neuropathic hyperalgesia is definedas:

${\%\mspace{14mu}{reversal}} = {\frac{\begin{matrix}\left\lbrack {\left( {{post}\mspace{14mu}{administration}{\mspace{11mu}\;}{PWT}} \right) -} \right. \\\left. \left( {{pre}\text{-}{administration}\mspace{14mu}{PWT}} \right) \right\rbrack\end{matrix}}{\left\lbrack {\left( {{baseline}\mspace{14mu}{PWT}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu}{PWT}} \right)} \right\rbrack} \times 100}$

In the Chung model, the spinal nerve ligation model of neuropathic painis used to produce mechanical hyperalgesia, thermal hyperalgesia andtactile allodynia in rats. Surgery is performed under isoflurane/O₂inhalation anesthesia. Following induction of anesthesia a 3 cm incisionis made and the left paraspinal muscles are separated from the spinousprocess at the L₄-S₂ levels. The L₆ transverse process is carefullyremoved with a pair of small rongeurs to identify visually the L₄-L₆spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) is (are)isolated and tightly ligated with silk thread. A complete hemostasis isconfirmed and the wound is sutured using non-absorbable sutures, such asnylon sutures or stainless steel staples. Sham-treated rats undergo anidentical surgical procedure except that the spinal nerve(s) is (are)not manipulated. Following surgery animals are weighed, administered asubcutaneous (s.c.) injection of saline or ringers lactate, the woundarea is dusted with antibiotic powder and they are kept on a warm paduntil they recover from the anesthesia. Animals are then returned totheir home cages until behavioral testing begins. The animals areassessed for response to noxious mechanical stimuli by determining PWT,as described below, prior to surgery (baseline), then immediately priorto and 1, 3, and 5 hours after being administered a Compound of theInvention for the left rear paw of the animal. The animals can also beassessed for response to noxious thermal stimuli or for tactileallodynia, as described below. The Chung model for neuropathic pain isdescribed in Kim et al., Pain 50(3):355-363 (1992).

Tactile Allodynia:

Sensitivity to non-noxious mechanical stimuli can be measured in animalsto assess tactile allodynia. Rats are transferred to an elevated testingcage with a wire mesh floor and allowed to acclimate for five to tenminutes. A series of von Frey monofilaments are applied to the plantarsurface of the hindpaw to determine the animal's withdrawal threshold.The first filament used possesses a buckling weight of 9.1 gms (0.96 logvalue) and is applied up to five times to see if it elicits a withdrawalresponse. If the animal has a withdrawal response, then the nextlightest filament in the series would be applied up to five times todetermine if it also could elicit a response. This procedure is repeatedwith subsequent lesser filaments until there is no response and theidentity of the lightest filament that elicits a response is recorded.If the animal does not have a withdrawal response from the initial 9.1gms filament, then subsequent filaments of increased weight are applieduntil a filament elicits a response and the identity of this filament isrecorded. For each animal, three measurements are made at every timepoint to produce an average withdrawal threshold determination. Testscan be performed prior to, and at 1, 2, 4 and 24 hours post drugadministration.

Mechanical Hyperalgesia:

Sensitivity to noxious mechanical stimuli can be measured in animalsusing the paw pressure test to assess mechanical hyperalgesia.

In rats, hind paw withdrawal thresholds (“PWT”), measured in grams, inresponse to a noxious mechanical stimulus are determined using ananalgesymeter (Model 7200, commercially available from Ugo Basile ofItaly), as described in Stein (Biochemistry & Behavior 31: 451-455(1988)). The rat's paw is placed on a small platform, and weight isapplied in a graded manner up to a maximum of 250 grams. The endpoint istaken as the weight at which the paw is completely withdrawn. PWT isdetermined once for each rat at each time point. PWT can be measuredonly in the injured paw, or in both the injured and non-injured paw. Inone non-limiting embodiment, mechanical hyperalgesia associated withnerve injury induced pain (neuropathic pain) can be assessed in rats.Rats are tested prior to surgery to determine a baseline, or normal,PWT. Rats are tested again 2 to 3 weeks post-surgery, prior to, and atdifferent times after (e.g. 1, 3, 5 and 24 hr) drug administration. Anincrease in PWT following drug administration indicates that the testcompound reduces mechanical hyperalgesia.

In Vivo Assay for Anticonvulsant Activity

Compounds of the Invention can be tested for in vivo anticonvulsantactivity after i.v., p.o., or i.p. injection using any of a number ofanticonvulsant tests in mice or rats, including the maximum electroshockseizure test (MES). Maximum electroshock seizures are induced in maleNSA mice weighing between 15-20 g and in male Sprague-Dawley ratsweighing between 200-225 g by application of current (for mice: 50 mA,60 pulses/sec, 0.8 msec pulse width, 1 sec duration, D.C.; for rats: 99mA, 125 pulses/sec, 0.8 msec pulse width, 2 sec duration, D.C.) using aUgo Basile ECT device (Model 7801). Mice are restrained by gripping theloose skin on their dorsal surface and saline-coated corneal electrodesare held lightly against the two corneae. Rats are allowed free movementon the bench top and ear-clip electrodes are used. Current is appliedand animals are observed for a period of up to 30 seconds for theoccurrence of a tonic hindlimb extensor response. A tonic seizure isdefined as a hindlimb extension in excess of 90 degrees from the planeof the body. Results can be treated in a quantal manner.

Pharmaceutical Compositions

Compounds of the Invention can be administered to a mammal in the formof a raw chemical without any other components present. Compounds of theInvention can also be administered to a mammal as part of apharmaceutical composition containing the compound combined with asuitable pharmaceutically acceptable carrier. Such a carrier can beselected from pharmaceutically acceptable excipients and auxiliaries.

Pharmaceutical compositions within the scope of the present disclosureinclude all compositions where a Compound of the Invention is combinedwith one or more pharmaceutically acceptable carriers. In oneembodiment, the Compound of the Invention is present in the compositionin an amount that is effective to achieve its intended therapeuticpurpose. While individual needs may vary, a determination of optimalranges of effective amounts of each compound is within the skill of theart. Typically, a Compound of the Invention can be administered to amammal, e.g., a human, orally at a dose of from about 0.0025 to about1500 mg per kg body weight of the mammal, or an equivalent amount of apharmaceutically acceptable salt, prodrug, or solvate thereof, per dayto treat the particular disorder. A useful oral dose of a Compound ofthe Invention administered to a mammal is from about 0.0025 to about 50mg per kg body weight of the mammal, or an equivalent amount of thepharmaceutically acceptable salt, prodrug, or solvate thereof. Forintramuscular injection, the dose is typically about one-half of theoral dose.

A unit oral dose may comprise from about 0.01 mg to about 1 g of theCompound of the Invention, e.g., about 0.01 mg to about 500 mg, about0.01 mg to about 250 mg, about 0.01 mg to about 100 mg, 0.01 mg to about50 mg, e.g., about 0.1 mg to about 10 mg, of the compound. The unit dosecan be administered one or more times daily, e.g., as one or moretablets or capsules, each containing from about 0.01 mg to about 1 g ofthe compound, or an equivalent amount of a pharmaceutically acceptablesalt, prodrug or solvate thereof.

A pharmaceutical composition of the present disclosure can beadministered to any animal that may experience the beneficial effects ofa Compound of the Invention. Foremost among such animals are mammals,e.g., humans and companion animals, although the disclosure is notintended to be so limited.

A pharmaceutical composition of the present disclosure can beadministered by any means that achieves its intended purpose. Forexample, administration can be by the oral, parenteral, subcutaneous,intravenous, intramuscular, intraperitoneal, transdermal, intranasal,transmucosal, rectal, intravaginal or buccal route, or by inhalation.The dosage administered and route of administration will vary, dependingupon the circumstances of the particular subject, and taking intoaccount such factors as age, gender, health, and weight of therecipient, condition or disorder to be treated, kind of concurrenttreatment, if any, frequency of treatment, and the nature of the effectdesired.

In one embodiment, a pharmaceutical composition of the presentdisclosure can be administered orally and is formulated into tablets,dragees, capsules or an oral liquid preparation. In one embodiment, theoral formulation comprises extruded multiparticulates comprising theCompound of the Invention.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered rectally, and is formulated in suppositories.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered by injection.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered transdermally.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered by inhalation or by intranasal or transmucosaladministration.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered by the intravaginal route.

A pharmaceutical composition of the present disclosure can contain fromabout 0.01 to 99 percent by weight, and preferably from about 0.25 to 75percent by weight, of active compound(s).

A method of the present disclosure, such as a method for treating adisorder responsive to the blockade of sodium channels in an animal inneed thereof, can further comprise administering a second therapeuticagent to the animal in combination with a Compound of the Invention. Inone embodiment, the other therapeutic agent is administered in aneffective amount.

Effective amounts of the other therapeutic agents are known to thoseskilled in the art. However, it is well within the skilled artisan'spurview to determine the other therapeutic agent's optimaleffective-amount range.

Compounds of the Invention (i.e., the first therapeutic agent) and thesecond therapeutic agent can act additively or, in one embodiment,synergistically.

Alternatively, the second therapeutic agent can be used to treat adisorder or condition that is different from the disorder or conditionfor which the first therapeutic agent is being administered, and whichdisorder or condition may or may not be a condition or disorder asdefined herein. In one embodiment, a Compound of the Invention isadministered concurrently with a second therapeutic agent; for example,a single composition comprising both an effective amount of a Compoundof the Invention and an effective amount of the second therapeutic agentcan be administered. Accordingly, the present disclosure furtherprovides a pharmaceutical composition comprising a combination of aCompound of the Invention, the second therapeutic agent, and apharmaceutically acceptable carrier. Alternatively, a firstpharmaceutical composition comprising an effective amount of a Compoundof the Invention and a second pharmaceutical composition comprising aneffective amount of the second therapeutic agent can be concurrentlyadministered. In another embodiment, an effective amount of a Compoundof the Invention is administered prior or subsequent to administrationof an effective amount of the second therapeutic agent. In thisembodiment, the Compound of the Invention is administered while thesecond therapeutic agent exerts its therapeutic effect, or the secondtherapeutic agent is administered while the Compound of the Inventionexerts its therapeutic effect for treating a disorder or condition.

The second therapeutic agent can be an opioid agonist, a non-opioidanalgesic, a non-steroidal anti-inflammatory agent, an antimigraineagent, a Cox-II inhibitor, a β-adrenergic blocker, an anticonvulsant, anantidepressant, an anticancer agent, an agent for treating addictivedisorder, an agent for treating Parkinson's disease and parkinsonism, anagent for treating anxiety, an agent for treating epilepsy, an agent fortreating a seizure, an agent for treating a stroke, an agent fortreating a pruritic condition, an agent for treating psychosis, an agentfor treating ALS, an agent for treating a cognitive disorder, an agentfor treating a migraine, an agent for treating vomiting, an agent fortreating dyskinesia, or an agent for treating depression, or a mixturethereof.

Examples of useful opioid agonists include, but are not limited to,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, proheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tilidine,tramadol, pharmaceutically acceptable salts thereof, and mixturesthereof.

In certain embodiments, the opioid agonist is selected from codeine,hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine,morphine, tramadol, oxymorphone, pharmaceutically acceptable saltsthereof, and mixtures thereof.

Examples of useful non-opioid analgesics include non-steroidalanti-inflammatory agents, such as aspirin, ibuprofen, diclofenac,naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, andpharmaceutically acceptable salts thereof, and mixtures thereof.Examples of other suitable non-opioid analgesics include the following,non limiting, chemical classes of analgesic, antipyretic, nonsteroidalantiinflammatory drugs: salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin; paraaminophennol derivatives including acetaminophen and phenacetin; indoleand indene acetic acids, including indomethacin, sulindac, and etodolac;heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac;anthranilic acids (fenamates), including mefenamic acid, andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);and alkanones, including nabumetone. For a more detailed description ofthe NSAIDs, see Paul A. Insel, Analgesic Antipyretic andAntiinflammatory Agents and Drugs Employed in the Treatment of Gout, inGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57(Perry B. Molinhoff and Raymond W. Ruddon eds., 9th ed 1996) and Glen R.Hanson, Analgesic, Antipyretic and Anti Inflammatory Drugs in Remington:The Science and Practice of Pharmacy Vol. II 1196-1221 (A. R. Gennaroed. 19th ed. 1995) which are hereby incorporated by reference in theirentireties. Suitable Cox-II inhibitors and 5-lipoxygenase inhibitors, aswell as combinations thereof, are described in U.S. Pat. No. 6,136,839,which is hereby incorporated by reference in its entirety. Examples ofuseful Cox II inhibitors include, but are not limited to, rofecoxib, andcelecoxib.

Examples of useful antimigraine agents include, but are not limited to,alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine,ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxoneacetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine,methysergide, metoprolol, naratriptan, oxetorone, pizotyline,propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone,zolmitriptan, and mixtures thereof.

Examples of useful β-adrenergic blockers include, but are not limitedto, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol,betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol,bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol,carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol,dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol,mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol,nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol,practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol,tertatolol, tilisolol, timolol, toliprolol, and xibenolol.

Examples of useful anticonvulsants include, but are not limited to,acetylpheneturide, albutoin, aloxidone, aminoglutethimide,4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate,calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,decimemide, diethadione, dimethadione, doxenitroin, eterobarb,ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin,5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate,mephenytoin, mephobarbital, metharbital, methetoin, methsuximide,5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin,narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione,phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide,phenylmethylbarbituric acid, phenytoin, phethenylate sodium, potassiumbromide, pregabaline, primidone, progabide, sodium bromide, solanum,strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,topiramate, trimethadione, valproic acid, valpromide, vigabatrin, andzonisamide.

Examples of useful antidepressants include, but are not limited to,binedaline, caroxazone, citalopram, (S)-citalopram, dimethazan,fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine,oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone,benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin,phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole,mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine,imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine,nortriptyline, noxiptilin, opipramol, pizotyline, propizepine,protriptyline, quinupramine, tianeptine, trimipramine, adrafinil,benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone,febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine,hematoporphyrin, hypericin, levophacetoperane, medifoxamine,milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline,prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride,sulpiride, tandospirone, thozalinone, tofenacin, toloxatone,tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine.

Examples of useful anticancer agents include, but are not limited to,acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin,aldesleukin, altretamine, ambomycin, ametantrone acetate,aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase,asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa,bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin,bleomycin sulfate, brequinar sodium, bropirimine, busulfan,cactinomycin, calusterone, caracemide, carbetimer, carboplatin,carmustine, carubicin hydrochloride, carzelesin, cedefingol,chlorambucil, cirolemycin, and cisplatin.

Therapeutic agents useful for treating an addictive disorder include,but are not limited to, methadone, desipramine, amantadine, fluoxetine,buprenorphine, an opiate agonist, 3-phenoxypyridine, or a serotoninantagonist.

Examples of useful therapeutic agents for treating Parkinson's diseaseand parkinsonism include, but are not limited to, carbidopa/levodopa,pergolide, bromocriptine, ropinirole, pramipexole, entacapone,tolcapone, selegiline, amantadine, and trihexyphenidyl hydrochloride.

Examples of useful therapeutic agents for treating anxiety include, butare not limited to, benzodiazepines, such as alprazolam, brotizolam,chlordiazepoxide, clobazam, clonazepam, clorazepate, demoxepam,diazepam, estazolam, flumazenil, flurazepam, halazepam, lorazepam,midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam,temazepam, and triazolam; non-benzodiazepine agents, such as buspirone,gepirone, ipsapirone, tiospirone, zolpicone, zolpidem, and zaleplon;tranquilizers, such as barbituates, e.g., amobarbital, aprobarbital,butabarbital, butalbital, mephobarbital, methohexital, pentobarbital,phenobarbital, secobarbital, and thiopental; and propanediol carbamates,such as meprobamate and tybamate.

Examples of useful therapeutic agents for treating epilepsy or seizureinclude, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproicacid, trimethadione, benzodiazepines, gamma-vinyl GABA, acetazolamide,and felbamate.

Examples of useful therapeutic agents for treating stroke include, butare not limited to, anticoagulants such as heparin, agents that break upclots such as streptokinase or tissue plasminogen activator, agents thatreduce swelling such as mannitol or corticosteroids, and acetylsalicylicacid.

Examples of useful therapeutic agents for treating a pruritic conditioninclude, but are not limited to, naltrexone; nalmefene; danazol;tricyclics such as amitriptyline, imipramine, and doxepin;antidepressants such as those given below; menthol; camphor; phenol;pramoxine; capsaicin; tar; steroids; and antihistamines.

Examples of useful therapeutic agents for treating psychosis include,but are not limited to, phenothiazines such as chlorpromazinehydrochloride, mesoridazine besylate, and thoridazine hydrochloride;thioxanthenes such as chloroprothixene and thiothixene hydrochloride;clozapine; risperidone; olanzapine; quetiapine; quetiapine fumarate;haloperidol; haloperidol decanoate; loxapine succinate; molindonehydrochloride; pimozide; and ziprasidone.

Examples of useful therapeutic agents for treating ALS include, but arenot limited to, baclofen, neurotrophic factors, riluzole, tizanidine,benzodiazepines such as clonazepan and dantrolene.

Examples of useful therapeutic agents for treating cognitive disordersinclude, but are not limited to, agents for treating dementia such astacrine; donepezil; ibuprofen; antipsychotic drugs such as thioridazineand haloperidol; and antidepressant drugs such as those given below.

Examples of useful therapeutic agents for treating a migraine include,but are not limited to, sumatriptan; methysergide; ergotamine; caffeine;and beta-blockers such as propranolol, verapamil, and divalproex.

Examples of useful therapeutic agents for treating vomiting include, butare not limited to, 5-HT3 receptor antagonists such as ondansetron,dolasetron, granisetron, and tropisetron; dopamine receptor antagonistssuch as prochlorperazine, thiethylperazine, chlorpromazine,metoclopramide, and domperidone; glucocorticoids such as dexamethasone;and benzodiazepines such as lorazepam and alprazolam.

Examples of useful therapeutic agents for treating dyskinesia include,but are not limited to, reserpine and tetrabenazine.

Examples of useful therapeutic agents for treating depression include,but are not limited to, tricyclic antidepressants such as amitryptyline,amoxapine, bupropion, clomipramine, desipramine, doxepin, imipramine,maprotiline, nefazadone, nortriptyline, protriptyline, trazodone,trimipramine, and venlafaxine; selective serotonin reuptake inhibitorssuch as citalopram, (S)-citalopram, fluoxetine, fluvoxamine, paroxetine,and setraline; monoamine oxidase inhibitors such as isocarboxazid,pargyline, phenelzine, and tranylcypromine; and psychostimulants such asdextroamphetamine and methylphenidate.

A pharmaceutical composition of the present disclosure is manufacturedin a manner which itself will be known in view of the instantdisclosure, for example, by means of conventional mixing, granulating,dragee-making, dissolving, extrusion, or lyophilizing processes. Thus,pharmaceutical compositions for oral use can be obtained by combiningthe active compound with solid excipients, optionally grinding theresulting mixture and processing the mixture of granules, after addingsuitable auxiliaries, if desired or necessary, to obtain tablets ordragee cores.

Suitable excipients include fillers such as saccharides (for example,lactose, sucrose, mannitol or sorbitol), cellulose preparations, calciumphosphates (for example, tricalcium phosphate or calcium hydrogenphosphate), as well as binders such as starch paste (using, for example,maize starch, wheat starch, rice starch, or potato starch), gelatin,tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodiumcarboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, one ormore disintegrating agents can be added, such as the above-mentionedstarches and also carboxymethyl-starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodiumalginate.

Auxiliaries are typically flow-regulating agents and lubricants such as,for example, silica, talc, stearic acid or salts thereof (e.g.,magnesium stearate or calcium stearate), and polyethylene glycol. Drageecores are provided with suitable coatings that are resistant to gastricjuices. For this purpose, concentrated saccharide solutions can be used,which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. In order to producecoatings resistant to gastric juices, solutions of suitable cellulosepreparations such as acetylcellulose phthalate orhydroxypropymethyl-cellulose phthalate can be used. Dye stuffs orpigments can be added to the tablets or dragee coatings, for example,for identification or in order to characterize combinations of activecompound doses.

Examples of other pharmaceutical preparations that can be used orallyinclude push-fit capsules made of gelatin, or soft, sealed capsules madeof gelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain a compound in the form of granules, which can bemixed with fillers such as lactose, binders such as starches, and/orlubricants such as talc or magnesium stearate and, optionally,stabilizers, or in the form of extruded multiparticulates. In softcapsules, the active compounds are preferably dissolved or suspended insuitable liquids, such as fatty oils or liquid paraffin. In addition,stabilizers can be added.

Possible pharmaceutical preparations for rectal administration include,for example, suppositories, which consist of a combination of one ormore active compounds with a suppository base. Suitable suppositorybases include natural and synthetic triglycerides, and paraffinhydrocarbons, among others. It is also possible to use gelatin rectalcapsules consisting of a combination of active compound with a basematerial such as, for example, a liquid triglyceride, polyethyleneglycol, or paraffin hydrocarbon.

Suitable formulations for parenteral administration include aqueoussolutions of the active compound in a water-soluble form such as, forexample, a water-soluble salt, alkaline solution, or acidic solution.Alternatively, a suspension of the active compound can be prepared as anoily suspension. Suitable lipophilic solvents or vehicles for such assuspension may include fatty oils (for example, sesame oil), syntheticfatty acid esters (for example, ethyl oleate), triglycerides, or apolyethylene glycol such as polyethylene glycol-400 (PEG-400). Anaqueous suspension may contain one or more substances to increase theviscosity of the suspension, including, for example, sodiumcarboxymethyl cellulose, sorbitol, and/or dextran. The suspension mayoptionally contain stabilizers.

The following examples are illustrative, but not limiting, of thecompounds, compositions, and methods of the present disclosure. Suitablemodifications and adaptations of the variety of conditions andparameters normally encountered in clinical therapy and which areobvious to those skilled in the art in view of this disclosure arewithin the spirit and scope of the disclosure.

EXAMPLES Example 1 Synthesis of2-(4-(4-chloro-2-fluorophenoxy)phenyl)-4,4,5-tetramethyl-1,3,2-dioxaborolane(Compound 6)

As shown in Scheme 1, a well stirred mixture of 4-chloro-2-fluorophenol(1) (14.62 g, 99.8 mmol), 1-fluoro-4-nitrobenzene (2) (12.80 g, 90.72mmol) and sodium carbonate (19.23 g, 181.43 mmol) in DMF (100 mL) washeated at 100° C. for 12 h. LC/MS showed that the reaction was complete.The cooled reaction mixture was poured into 350 mL of water withstirring and extracted with 2×100 mL of dichloromethane. The combinedorganic layers were dried (MgSO₄) and concentrated under reducedpressure to give the crude product. Purification by chromatographyyielded 24.2 g (99%) of 4-chloro-2-fluoro-1-(4-nitrophenoxy)benzene (3)as a pale yellow solid. ¹H NMR CDCl₃: 8.25-8.18 (m, 2H); 7.28-7.15 (m,3H); 7.08-6.97 (m, 2H). Unless otherwise indicated all NMR chemicalshifts reported herein are denoted by the delta (δ) scale.

To a well stirred suspension of4-chloro-2-fluoro-1-(4-nitrophenoxy)benzene (3) (24.0 g, 89.67 mmol) inethanol (180 mL) was added Pd on carbon (50% water, 4.8 g 2.5 mole %)and the reaction mixture was cooled to 0° C. internal temperature. Solidsodium borohydride (4.07 g, 89.67 mmol) was added at a rate such thatthe internal temperature remained below 25° C. After addition, thereaction mixture was stirred at room temperature for 30 minutes. LC/MSshowed that the reaction was complete. The reaction mixture was dilutedwith ethyl acetate (80 mL), filtered through a pad of Celite, the Celitewas washed with ethyl acetate, and the combined organic fractions wereconcentrated to yield the crude aniline as a brown paste. The crudeproduct was dissolved in hot acetonitrile (150 mL) and a hot solution oftosic acid hydrate (17.91 g, 1.05 eq.) in acetonitrile (25 mL) wasadded. The resulting solution was stirred and allowed to cool to roomtemperature. The resulting tan solid was isolated by vacuum filtration,washed with acetonitrile and allowed to dry to yield4-(4-chloro-2-fluorophenoxy)aniline as the tosic acid salt (4a) (32.2 g,87%). LC/MS: m/z=238 [M+H]⁺.

To a well stirred suspension of 4-(4-chloro-2-fluorophenoxy)anilinetosic acid salt (4a) (32.2 g, 78.56 mmol) and tosic acid hydrate (29.89g 157.1 mmol) in acetonitrile (630 mL) cooled to 0° C. internaltemperature was added a solution of sodium nitrite (11 g, 157 mmol) andpotassium iodide (32.6 g, 196.4 mmol) in water (157 mL) at a rate suchthat the reaction temperature remained below 25° C. and any foaming wascontrolled. After the addition was complete, the reaction mixture wasstirred at room temperature an additional two hours. LC/MS showed thatthe reaction was complete. The acetonitrile was removed under reducedpressure, and the residue was partitioned between dichloromethane andaqueous sodium sulfite. The layers were separated and the aqueous layerwas extracted 2×50 mL with dichloromethane. The combined organic layerswere dried (MgSO₄) and concentrated to yield the crude product as abrown oil. Purification by chromatography (silica gel DCM in hexanes 0%to 15%) yielded 15.7 g (57%) of pure4-chloro-2-fluoro-1-(4-iodophenoxy)benzene (5). ¹H NMR CDCl₃: 7.82-7.58(m, 2H); 7.22-7.18 (m, 1H); 7.12-7.08 (m, 1H); 7.02-6.88 (m, 1H);6.75-6.48 (m, 2H).

A suspension of 4-chloro-2-fluoro-1-(4-iodophenoxy)benzene (5) (15.0 g,43.04 mmol), pinacol diborane (12.57 g, 49.5 mmol), and potassiumacetate (12.67 g, 129 mmol) in DMF (86 mL) was degassed under reducedpressure and flushed with argon three times.[1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (1.23 g,1.51 mmol) was added and the reaction was heated at 80° C. under inertatmosphere for 4 hours. LC/MS indicated that the reaction was complete.The cooled reaction mixture was poured into water and extracted 3×50 mLwith dichloromethane. The combined organic layers were dried (MgSO₄) andconcentrated under reduced pressure to give the crude product.Purification by chromatography (silica gel 2/1 hexanes/DCM) yielded 7.6g (50%) of pure2-(4-(4-chloro-2-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(6). ¹H NMR CDCl₃: 7.80-7.75 (m, 2H); 7.22-7.18 (m, 1H); 7.12-7.08 (m,1H); 7.02-6.88 (m, 1H); 6.95-6.90 (m, 2H).

Example 2 Synthesis of(R)-2-(4-(5-chloro-2-fluorophenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide(Compound Example No. 7)

As shown in Scheme 2, a mixture of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (12) (Aldrich, 4.6g, 21 mmol), 4-chloro-1,2-difluorobenzene (13) (Aldrich, 3.09 g, 22mmol) and Cs₂CO₃ (Aldrich, 8.6 g, 26 mmol) in DMF (20 mL) was heated at120° C. for 12 hours. After cooling to room temperature, the mixture waspurified using Combiflash (80 g silica gel, 0-10% EtOAc/Hexane) to give2-(4-(5-chloro-2-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,3-dioxaborolane(14) (1.8 g).

A sealed pressure bottle containing a mixture of methyl2,6-dichloropyrimidine-4-carboxylate (7) (Aldrich, 1 g, 4.83 mmol),4,4,5,5-tetrametyl-2-vinyl-1,3,2-dioxaborolane (8) (Aldrich, 1.2 mL, 7.0mmol), PdCl₂(PPh₃)₂ (Aldrich, 315 mg, 0.39 mmol), and Cs₂CO₃ (Aldrich,3.15 g, 9.6 mmol) in DME (5 mL), EtOH (2 mL), and H₂O (5 mL) was heatedat 70° C. for 3.5 hours. After cooling to room temperature, the mixturewas diluted with EtOAc (100 mL) and brine (50 mL). The mixture wasadjusted to pH 1 with 4N aqueous HCl solution. After separation, theaqueous layer was further extracted with EtOAc (2×50 mL) and thecombined organic layers were dried with Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified usingCombiflash (12 g silica gel, 0˜100% EtOAc/Hexane) to give compound 9(800 mg) as red liquid.

A sealed pressure bottle containing compound 9 (956 mg, 5.2 mmol),2-(4-(5-chloro-2-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,3-dioxaborolane(14) (1.8 g, 5.2 mmol), PdCl₂(PPh₃)₂ (292 mg, 0.42 mmol), and Cs₂CO₃(3.4 g, 10.4 mmol) in DME (6 mL), EtOH (3 mL), and H₂O (6 mL) was heatedat 95° C. for 4 hours. After cooling to room temperature, the mixturewas adjusted to pH 4 with 4N HCl aqueous solution. The mixture wasextracted with EtOAc (2×50 mL) and the combined organic layers weredried with Na₂SO₄, filtered, and concentrated to dryness under reducedpressure. To the residue was added Et₂O. The mixture was sonicated andthe solid was collected to give pure compound 10 (800 mg). The Et₂Osolution was concentrated and triturated with EtOAc in hexane to obtainadditional compound 10.

To a solution of compound 10 (800 mg, 2.2 mmol) in DMF at 0° C. wasadded HBTU (983 mg, 2.6 mmol), (NH₄)₂CO₃ (422 mg, 4.4 mmol), and DIEA(1.2 mL, 6.6 mmol). The mixture was allowed to warm to room temperatureslowly over 2 h with stirring. The mixture was extracted with EtOAc(2×100 mL) and the combined organic layers were dried with Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified using Combiflash (40 g silica gel, 0˜40% EtOAc/Hexane, then 12g silica gel, 0˜40% EtOAc/Hexane) to give pure compound 11 (180 mg).

To a solution of compound 11 (91 mg, 0.24 mmol) in iPrOH (2 mL) at 0° C.was added H₂O (2 mL). To the resulting white milky suspension was addedAD-Mix-β (1.2 g). The resulting mixture was vigorously stirred at roomtemperature for 2 days. The mixture was extracted with EtOAc (3×50 mL)and the combined organic layers were dried with Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified usingCombiflash (4 g silica gel, 0-60% EtOAc/Hexane) to give(R)-2-(4-(5-chloro-2-fluorophenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide(Compound Example No. 7) (40 mg) as white solid. ¹H NMR (400 MHz,CD₃OD): 8.51 (2H, d, J=8.8 Hz), 8.03 (1H, s), 7.22-7.12 (3H, m), 6.99(2H, d, J=9.2 Hz), 4.74 (1H, dd, J=3.6, 5.6 Hz), 3.89 (1H, dd, J=4.0,11.6 Hz), 3.76 (1H, dd, J=5.6, 11.2 Hz); LC/MS: m/z=404[M+H]⁺.

(S)-2-(4-(5-chloro-2-fluorophenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide(Compound Example No. 8) was prepared in a similar fashion to(R)-2-(4-(5-chloro-2-fluorophenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide(Compound Example No. 7) using AD-Mix-α instead of AD-Mix-β. ¹H NMR (400MHz, CD3OD): 8.64 (2H, d, J=9.2 Hz), 8.17 (1H, s), 7.35-7.24 (3H, m),7.11 (2H, d, J=12 Hz), 4.86 (1H, dd, J=3.6, 5.6 Hz), 4.02 (1H, dd,J=4.0, 11.6 Hz), 3.89 (1H, dd, J=5.6, 11.2 Hz); LC/MS: rn/z=404[M+H]⁺.

(R)-2-(4-(4-chloro-2-fluorophenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide(Compound Example No. 9) was prepared in a similar fashion to(R)-2-(4-(5-chloro-2-fluorophenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide(Compound Example No. 7) using2-(4-(4-chloro-2-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,3-dioxaborolane(6) instead of2-(4-(5-chloro-2-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,3-dioxaborolane(14). ¹H NMR (400 MHz, CD₃OD): 8.49 (2H, d, J=8.8 Hz), 8.03 (1H, s),7.30 (1H, dd, J=2.8, 10 Hz), 7.18-7.10 (2H, m), 6.96 (2H, d, J=9.2 Hz),4.73 (1H, dd, J=3.2, 5.6 Hz), 3.89 (1H, dd, J=3.6, 11 Hz), 3.75 (1H, dd,J=6.0, 11 Hz); LC/MS: nm/z=404[M+H]⁺. Compound 6 was prepared accordingto Scheme 1 in Example 1.

(S)-2-(4-(4-chloro-2-fluorophenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide(Compound Example No. 10) was prepared in a similar fashion to(R)-2-(4-(4-chloro-2-fluorophenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide(Compound Example No. 9) using AD-mix-α instead of AD-Mix-β. ¹H NMR (400MHz, CD3OD): 8.49 (2H, d, J=8.8 Hz), 8.03 (1H, s), 7.30 (1H, dd, J=2.4,10 Hz), 7.18-7.10 (2H, m), 6.96 (2H, d, J=9.2 Hz), 4.73 (1H, dd, J=3.6,6.4 Hz), 3.89 (1H, dd, J=3.6, 11 Hz), 3.75 (1H, dd, J=6.0, 11 Hz);LC/MS: m/z=404[M+H]⁺.

Example 3 Synthesis of(R)-4-(1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)pyrimidine-2-carboxamide(Compound Example No. 20)

As shown in Scheme 3, a sealed pressure bottle containing compound 15(Aldrich, 1 g, 5.2 mmol), compound 16 (1.62 g, 5.4 mmol), PdCl₂(PPh₃)₂(290 mg, 0.41 mmol), and Cs₂CO₃ (3.4 g, 10.4 mmol) in DME (16 mL),ethanol (8 mL), and H₂O (16 mL) was heated at 60° C. for 3 h. Aftercooling, the mixture was diluted with EtOAc (200 mL) and brine (100 mL).After separation, the organic layer was dried with Na₂SO₄, filtered, andconcentrated under reduced pressure to give compound 17 as yellow solid.

Compound 17 was dissolved in methanol (50 mL) and 2N HCl in dioxane (2mL) was added. The resulting solution was stirred at room temperaturefor 12 h. After removing the methanol, the residue was diluted withEtOAc (200 mL) and washed successively with brine (100 mL), NaHCO₃solution, (100 mL), and brine (100 mL). The organic layer was dried withNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified using Combiflash (80 g silica gel, 0˜50% EtOAc in hexane)to give compound 18 as light yellow solid (1.4 g).

A sealed vial containing a solution of compound 18 (1.4 g, 3.9 mmol),compound 8 (1.2 mL, 7 mmol), and PdCl₂(dppf)₂(255 mg, 0.31 mmol) in TBAF(Aldrich, 12 mL, 1 M THF solution) was heated at 70° C. for 3 hours.After cooling to room temperature, the mixture was purified usingCombiflash (40 g silica gel, 0˜50% EtOAc in hexanes) to give compound 19(211 mg) as a solid. The corresponding acid was also formed but notisolated.

To a mixture of compound 19 (105 mg, 0.3 mmol) in i-PrOH (2 mL) and H₂O(2 mL) at 0° C. was added AD-Mix-β (392 mg) and the resulting mixturewas stirred vigorously for 12 h. Only compound 20 was observed in thereaction. The reaction mixture was extracted with EtOAc (5 mL) and theaqueous layer was freeze-dried. The material thus obtained was washedwith methanol (2×10 mL) and filtered. To the filtrate was added 2 N HClin dioxane (1 mL) and the resulting material was stirred at roomtemperature for 12 h. After removing the methanol, the residue waspurified using Combiflash (12 g silica gel, 0˜100% EtOAc in hexanes) togive compound 21 (56 mg) as clear oil.

Compound 21 (56 mg, 0.14 mmol) was dissolved in 7 N NH₃ in methanol (5mL) at room temperature and stirred for 12. The solvent was removedunder reduced pressure to give(R)-4-(1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)pyrimidine-2-carboxamide(Compound Example No. 20). ¹H NMR (400 MHz, CD₃OD): 8.50 (2H, d, J=9.2Hz), 8.34 (1H, s), 7.35-7.24 (6H, m), 5.01 (1H, m), 4.10 (1H, dd, J=4.4,12 Hz), 4.02 (1H, dd, J=5.2, 12 Hz); LC/MS: m/z=370[M+H]⁺.

(S)-4-(1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)pyrimidine-2-carboxamide(Compound Example No. 21) was prepared in a similar fashion to(R)-4-(1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)pyrimidine-2-carboxamide(Compound Example No. 20) using AD-Mix-α instead of AD-Mix-β. ¹H NMR(400 MHz, CD₃OD): 8.25 (2H, d, J=8.8 Hz), 8.09 (1H, s), 7.09-6.98 (6H,m), 4.75 (1H, m), 4.10 (1H, dd. J=3.6, 12 Hz), 3.77 (1H, dd, J=5.2, 12Hz); LC/MS: m/z=370[M+H]⁺.

Example 4 Synthesis of(S)-6-(1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide(Compound Example No. 1)

As shown in Scheme 4, a suspension of2-chloro-6-vinylpyrimidine-4-carboxylic acid (9) (4.38 g, 0.02 mol),2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(22) (7.45 g, 0.02 mol), Na₂CO₃ (5.3 g, 0.05 mol), and PdCl₂(PPh₃)₂(Aldrich, 701 mg, 1.0 mmol) in dimethoxy ethane(DME)/EtOH/H₂O (500 mL,2:1:2 ratio) was degassed by repeating with Ar₂/vacuum cycles. Themixture was heated at 90° C. for 23 h. Upon cooling to the roomtemperature, the mixture was poured into DCM. The solids were filteredoff and the filtrates were washed with H₂O and the aqueous phase wasextracted with EtOAc. The combined organic layers were dried withanhydrous MgSO₄ and concentrated to give2-(4-(4-fluorophenoxy)phenyl)-6-vinylpyrimidine-4-carboxylic acid (23)pale yellow oil which was then purified by column chromatography(EtOAc:Hexanes=1:1) to give 6.5 g (82% yield), Rf=0.3 (DCM: MeOH=9:1);LC/MS: m/z=337 [M+H]⁺.

2-(4-(4-fluorophenoxy)phenyl)-6-vinylpyrimidine-4-carboxylic acid (23)(580 mg, 1.73 mmol), HOBt (279.5 mg, 2.07 mmol), and EDC (395.4 mg, 2.07mmol) in dry dichloromethane were stirred for 20 minutes at roomtemperature and MeOH (3.46 mL, 86.5 mmol) was added thereto. After thereaction was complete, the solvent was removed in vacuo. The residue wasdissolved in dichloromethane which was then washed with H₂O. The organiclayer was dried over anhydrous MgSO₄ and concentrated to give oilyresidue. The resulting oil was purified by Combiflash (50% EtOAc inHexanes) to give methyl2-(4-(4-fluorophenoxy)phenyl)-6-vinylpyrimidine-4-carboxylate (24) (568mg, 94% yield). ¹H NMR (400 MHz, CD₃OD): 8.45 (2H, d, J=8.5 Hz), 7.74(1H, s), 6.90-7.01 (6H, m), 6.77-6.86 (1H, dd, J=11, 18 Hz), 6.60 (1H,d, J=17 Hz), 5.7 (1H, d, J=10.5 Hz), 3.98 (3H, s); LC/MS: m/z=351[M+H]⁺.

(S)-6-(1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxylicacid (25) was prepared in a similar fashion to compound 20 (Scheme 3)using AD mix-α (1.51 g) and compound 24 (360 mg, 1.03 mmol) in aqueousisopropyl alcohol (i-PrOH: H₂O=1:1). (304 mg, 80% yield); LC/MS: m/z=371[M+H]⁺.

(S)-methyl6-(1,2-dihydroxyethyl)-2-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxylate(26) was prepared in a similar fashion to compound 21 (Scheme 3) usingcompound 25 (89 mg, 0.24 mmol), 4N HCl/dioxane (1.0 mL) and MeOH (2 mL).(90 mg, 97% yield). Rf=0.5 (EtOAc: Hexanes=1:1); LC/MS: m/z=385[M+H]⁺.

(S)-6-(1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide(Compound Example No. 1) was prepared in a similar fashion to(R)-4-(1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)pyrimidine-2-carboxamideusing compound 26 (90 mg, 0.23 mmol). (67 mg, 79%). ¹H NMR (400 MHz,CD₃OD): 8.60 (2H, d, J=8.9 Hz), 8.15 (1H, s), 7.04-7.22 (6H, m),6.77-6.86 (1H, dd, J=11, 18 Hz), 6.60 (1H, d, J=17 Hz), 5.7 (1H, d,J=10.5 Hz), 3.98 (3H, s); LC/MS: m/z=370[M+H]⁺.

(R)-6-(1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide(Compound Example No. 2) was prepared in a similar fashion to(S)-6-(1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide(Compound Example No. 1) wherein the R-isomer of compound 33 (185 mg,0.48 mmol) was used to give the desired product as off-white solid (163mg, 92% yield). ¹H NMR (400 MHz, CD₃OD): 8.60 (2H, d, J=8.9 Hz), 8.15(1H, s), 7.04-7.22 (614, m), 4.84-4.85 (1H, m), 4.02 (1H, dd, J=3.9,11.4 Hz), 3.88 (1H, dd, J=3.9, 11.4 Hz), 3.98 (3H, s); LC/MS:m/z=370[M+H].

Example 5 Synthesis of(R)-2-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide(Compound Example No. 12)

4-Fluoro-2-(trifluoromethyl)benzonitrile (53 g, 280.4 mmol, AKScientific) was treated with 4-iodophenol (61.7 g, 280.4 mmol, Aldrich)and sodium carbonate (44.6 g, 420.6 mmol) in 90 mL anhydrous DMF at 100°C. for 20 hours. The reaction mixture was diluted with 250 mL water andextracted with 2×200 mL EtOAc. The combined organic layers were driedover sodium sulfate and concentrated under reduced pressure to give4-(4-iodophenoxy)-2-(trifluoromethyl)benzonitrile as a white solid (75g, 69%). ¹H NMR (400 MHz, CDCl₃): 7.80-7.72 (3H, m), 7.36-7.32 (1H, m),7.17-7.10 (1H, m), 6.89-6.82 (2H, m).

4-(4-Iodophenoxy)-2-trifluoromethyl benzonitrile (20 g, 51.4 mmol) wastreated with bis-pinacol boronate (13 g, 51.4 mmol, NetChem), KOAc (10g, 102.8 mmol), and PdCl₂dppf*CH₂Cl₂ (2.1 g, 2.57 mmol) in 50 mL dioxaneat 100° C. for 20 hours. The reaction mixture was diluted with 500 mLwater and extracted with 2×300 mL EtOAc. The combined organic layerswere washed with 250 mL brine, dried over sodium sulfate, andconcentrated under reduced pressure. The residue was chromatographed onsilica using a gradient of EtOAc (20% max) in hexane as the eluent togive4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-(trifluoromethyl)benzonitrile(11.45 g, 57%). ¹H NMR (400 MHz, CDCl₃): 7.93-7.86 (2H, m), 7.79-7.71(1H, m), 7.36-7.32 (1H, m), 7.17-7.12 (1H, m), 7.10-7.04 (2H, m),1.38-1.34 (12H, s).

A 100 mL round bottom flask was charged with4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-(trifluoromethyl)benzonitrile(1.5 g, 3.86 mmol), 2-chloro-6-vinylpyrimidine-4-carboxylic acid (709.5mg, 3.86 mmol), PdCl₂(PPh₃)₂ (190 mg, 0.27 mmol), and cesium carbonate(2.5 g, 7.72 mmol) in DME (8 mL), EtOH (4 mL), and water (8 mL). Thereaction mixture was heated to 90° C. for 10 hours. The reaction mixturewas diluted with 100 mL water, acidified to pH 5 with aqueous 4N HCl,and extracted with 2×100 mL EtOAc. The combined organic layers weredried over sodium sulfate and concentrated to give2-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-6-vinylpyrimidine-4-carboxylicacid as a light brown solid. The material was used in the next stepwithout purification. LC/MS: m/z=412 [M+H]⁺.

In a 50-mL vial with a screw-top septum2-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-6-vinylpyrimidine-4-carboxylic acid (340 mg, 0.83 mmol)was dissolved in DMF (5 mL) and treated with potassium carbonate (343.6mg, 2.49 mmol) and iodomethane (0.5 mL). The mixture was stirred at roomtemperature for three hours, diluted with 100 mL water, and extractedwith 2×50 mL diethyl ether. The combined organic layers were dried oversodium sulfate and concentrated under reduced pressure to provide methyl2-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-6-vinylpyrimidine-4-carboxylate. The residue was used inthe next step without purification. LC/MS: m/z=426 [M+H]⁺.

In a 50-mL vial with a screw-top septum, methyl2-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-6-vinylpyrimidine-4-carboxylatewas dissolved in MeOH (2 mL) and stirred at room temperature. To thesolution was added 7N NH₃/MeOH (5 mL) and the reaction mixture wasstirred for 20 hours. The reaction mixture was concentrated underreduced pressure and purified using Combiflash with a gradient ofmethanol (30% max) in chloroform to provide2-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-6-vinylpyrimidine-4-carboxamide(270 mg) as a white solid. LC/MS: m/z=411 [M+H]⁺.

In a 50-mL vial with a screw-top septum was suspended2-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-6-vinylpyrimidine-4-carboxamide(50 mg, 0.12 mmol) in isopropanol (5 mL) and water (5 mL). To thesuspension was added AD Mix beta (200 mg) in one portion. The mixturewas stirred at room temperature for 18 hours, diluted with 50 mL water,and extracted with 2×50 mL EtOAc. The combined organic layers were driedover sodium sulfate and concentrated under reduced pressure. The residuewas chromatographed using methanol (40% max) in chloroform as the eluentto provide (R)-2-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide (12 mg)as a white solid. ¹H NMR (400 MHz, DMSO-d6): 8.79-8.73 (2H, m),8.68-8.63 (1H, m), 8.21-8.17 (1H, m), 8.07-8.03 (1H, m), 8.02-7.97 (1H,m), 7.67-7.62 (1H, m), 7.49-7.43 (1H, m), 7.42-7.35 (2H, m), 5.85-5.81(1H, m), 4.87-4.81 (1H, m), 4.75-4.68 (1H, m), 3.86-3.78 (1H, m),3.73-3.65 (1H, m); LC/MS: m/z=445 [M+H]⁺.

(S)-2-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide(Compound Example No. 13) was prepared in a similar fashion to(R)-2-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-6-(1,2-dihydroxy-ethyl)pyrimidine-4-carboxamide(Compound Example No. 12) using AD-Mix alpha instead of AD-Mix beta. ¹HNMR (400 MHz, DMSO-d6) δ 8.80-8.70 (2H, m), 8.69-8.61 (1H, m), 8.23-8.15(1H, m), 8.07-8.02 (1H, m), 8.01-7.96 (1H, m), 7.67-7.60 (1H, m),7.49-7.41 (1H, m), 7.42-7.34 (2H, m), 5.86-5.78 (1H, m), 4.87-4.79 (1H,m), 4.75-4.66 (1H, m), 3.85-3.76 (1H, m), 3.74-3.63 (1H, m); LC/MS:m/z=445 [M+H]⁺.

(R)-6-(1,2-dihydroxyethyl)-2-(4-(4-(trifluoromethyl)phenoxy)phenyl)pyrimidine-4-carboxamide(Compound Example No. 18) was prepared a similarly to(R)-2-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide(Compound Example No. 12) using4,4,5,5-tetramethyl-2-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1,3,2-dioxaborolane.¹H NMR (400 MHz, DMSO-d₆): 8.75-8.67 (2H, m), 8.65-8.59 (1H, m),8.05-8.01 (1H, m), 8.01-7.94 (1H, m), 7.83-7.75 (2H, m), 7.31-7.22 (4H,m), 5.84-5.79 (1H, m), 4.87-4.79 (1H, m), 4.73-4.67 (1H, m), 3.86-3.77(1H, m), 3.74-3.64 (1H, m); LC/MS: m/z=420 [M+H]⁺.

(S)-6-(1,2-dihydroxyethyl)-2-(4-(4-(trifluoromethyl)phenoxy)phenyl)pyrimidine-4-carboxamide(Compound Example No. 17) was prepared in a similar fashion to(R)-6-(1,2-dihydroxyethyl)-2-(4-(4-(trifluoromethyl)phenoxy)phenyl)pyrimidine-4-carboxamide(Compound Example No. 18) using AD-Mix-α instead of AD-Mix-β. ¹H NMR(400 MHz, DMSO-d₆): 8.77-8.66 (2H, m), 8.66-8.56 (1H, m), 8.06-8.00 (1H,m), 8.00-7.94 (1H, m), 7.84-7.73 (2H, m), 7.31-7.20 (4H, m), 5.85-5.77(1H, m), 4.88-4.78 (1H, m), 4.74-4.64 (1H, m), 3.87-3.76 (1H, m),3.73-3.63 (1H, m); LC/MS: m/z=420 [M+H]⁺.

Example 6 Synthesis ofN—((S)-1-amino-1-oxopropan-2-yl)-6-((S)-1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide(Compound Example No. 16)

A mixture of orotic acid mono hydrate (34.828 g, 200.0 mmol), phosphorusoxychloride (100 mL, 1092 mmol) and 20 drops of DMF were heated at 110°C. overnight. After cooling, the dark mixture was treated with 500 mLhexanes and vigorously stirred. The hexane layer was decanted andquickly washed with water (1×100 mL) and brine (1×100 mL) and dried overMgSO₄. The organics were filtered and carefully evaporated in vacuo togive 2,6-dichloropyrimidine-4-carbonyl chloride as a light yellow liquid(26.13 g, 123.6 mmol, 62% yield). ¹H NMR (400 MHz, CDCl₃): 7.93 (1H, s).

To a mixture of (S)-methyl 2-aminopropanoate hydrochloride (1.397 g,10.01 mmol) in DCM (80 mL) was added iPr₂NEt (4.35 mL, 24.97 mmol). Themixture was stirred for a few minutes and a solution of the2,6-dichloropyrimidine-4-carbonyl chloride (2.107 g, 9.97 mmol) in DCM(20 mL) was added over a period of 1 minute. After stirring overnight,the reaction was concentrated in vacuo to a residue. The residue waschromatographed over silica gel using 10-40% EtOAc in hexanes. Theproduct fractions were evaporated in vacuo to give (S)-methyl2-(2,6-dichloropyrimidine-4-carboxamido)propanoate as a yellow oil(0.921 g, 3.31 mmol, 33% yield). LC/MS: nm/z=278.1 [M+H]⁺.

To a mixture of (S)-methyl2-(2,6-dichloropyrimidine-4-carboxamido)propanoate (0.921 g, 3.31 mmol)in dioxane (10 mL) was added4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.65 mL, 3.8 mmol),Na₂CO₃ (0.704 g, 6.64 mmol), and PdCl₂(dppf) (0.142 g, 0.17 mmol). Thereaction vessel was flushed with argon, sealed, and heated at 80° C.overnight. Additional 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(0.65 mL, 3.8 mmol) was added. After 7 hours at 80° C., additional4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.65 mL, 3.8 mmol) wasadded. After stirring at 80° C. for 4 more days the reaction wasconcentrated in vacuo to a residue and chromatographed over silica gelusing 0-70% EtOAc in hexanes. The product fractions were evaporated invacuo to give (S)-methyl2-(2-chloro-6-vinylpyrimidine-4-carboxamido)propanoate as a yellow oil(0.444 g, 1.65 mmol, 50% yield). LC/MS: nm/z=270.2 [M+H]⁺.

To a solution of (S)-methyl2-(2-chloro-6-vinylpyrimidine-4-carboxamido)propanoate (0.444 g, 1.65mmol) in dioxane (10 mL) was added2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.521 g, 1.66 mmol), 2M aqueous Na₂CO₃ (1.65 mL, 3.30 mmol), andPdCl₂(dppf) (0.071 g, 0.087 mmol). The reaction vessel was flushed withargon, sealed and heated at 100° C. overnight. After cooling, thereaction mixture was evaporated in vacuo and the residue chromatographedover silica gel with 10-40% EtOAc in hexanes. The product fractions wereevaporated in vacuo to give (S)-methyl2-(2-(4-(4-fluorophenoxy)phenyl)-6-vinylpyrimidine-4-carboxamido)propanoateas a tan-yellow oil (0.304 g, 0.72 mmol, 44% yield). LC/MS: in/z=422.2[M+H]⁺.

To a warmed milky suspension of (S)-methyl2-(2-(4-(4-fluorophenoxy)phenyl)-6-vinylpyrimidine-4-carboxamido)propanoate(0.407 g, 0.966 mmol) in iPrOH (5 mL) and water (5 mL) was addedAD-Mix-α (1.328 g). After stirring 2.5 hours the reaction mixture waspartitioned between 25 mL water and 50 mL EtOAc. The organic layers wereisolated and the aqueous layer extracted once more with 25 mL EtOAc. Thecombined organic layers were dried over Na₂SO₄, filtered, and evaporatedin vacuo. The residue was chromatographed over silica gel using 50-100%EtOAc in hexanes. The product fractions were evaporated in vacuo to give(S)-methyl2-(6-((S)-1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamido)propanoate(Compound Example No. 14) as a cream-colored solid (0.236 g, 0.518 mmol,54% yield). ¹H NMR (400 MHz, DMSO-d₆): 9.39 (1H, d, J=7.9 Hz), 8.64 (2H,d, J=9.0 Hz), 8.00 (1H, s), 7.33-7.25 (2H, m), 7.22-7.16 (2H, m), 7.13(2H, d, J=9.0 Hz), 5.82 (1H, d, J=5.3 Hz), 4.83 (1H, t, J=6.1 Hz),4.72-4.60 (2H, m), 3.85-3.77 (1H, m), 3.72-3.63 (4H, m), 1.49 (3H, d,J=7.2 Hz); LC/MS: m/z=456.1 [M+H]⁺.

To a solution of (S)-methyl2-(6-((S)-1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamido)propanoate(0.100 g, 0.22 mmol) in 5:1 THF/water (5 mL) was added LiOH.H₂O (0.009g, 0.21 mmol). After stirring overnight additional LiOH.H₂O (0.001 g,0.02 mmol) was added. After 5 hours the reaction was evaporated invacuo. To the residue was added 5 mL water and 0.22 mL 1N HCl. Theresulting precipitate was filtered off, washed with water, and driedunder vacuum. The solid was triturated with 2 mL 20% EtOAc/hexanes,isolated, and rinsed with additional hexanes. The material was driedunder vacuum to give(S)-2-(6-((S)-1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamido)propanoic acid (Compound Example No. 15) as an off-white powder (0.062g, 0.14 mmol, 64% yield). ¹H NMR (400 MHz, DMSO-d₆): 12.82 (1H, s), 9.23(1H, d, J=7.9 Hz), 8.62 (2H, d, J=9.0 Hz), 8.00 (1H, s), 7.33-7.25 (2H,m), 7.23-7.16 (2H, m), 7.13 (2H, d, J=8.8 Hz), 5.82 (1H, d, J=5.3 Hz),4.83 (1H, t, J=5.9 Hz), 4.70 (1H, q, J=4.4 Hz), 4.55 (1H, p, J=7.5 Hz),3.84-3.76 (1H, m), 3.71-3.63 (1H, m), 1.48 (3H, d, J=7.2 Hz); LC/MS:m/z=442.1 [M+H]⁺.

To (S)-methyl2-(6-((S)-1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamido)propanoate(0.120 g, 0.263 mmol) was added MeOH (2.5 mL) and 7M NH₃ in MeOH (2.5mL, 17.5 mmol). The reaction was sealed, stirred overnight thenevaporated in vacuo. MeOH was added and the reaction mixture evaporatedagain in vacuo. The resulting solid was triturated with 4 mL 20%EtOAc/hexanes, filtered, and rinsed once with 2 mL 20% EtOAc/hexanes.The material was dried under vacuum to giveN—((S)-1-amino-1-oxopropan-2-yl)-6-((S)-1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide(Compound Example No. 16) as a pale peach-colored powder (0.099 g. 0.23mmol. 87% yield). ¹H NMR (400 MHz, DMSO-d₆): 8.99 (1H, d, J=7.7 Hz),8.55 (2H, d, J=9.0 Hz), 8.01 (1H, s), 7.60 (1H, s), 7.33-7.25 (2H, m),7.24-7.17 (3H, m), 7.14 (2H, d, J=8.8 Hz), 5.83 (1H, d, J=5.3 Hz), 4.83(1H, t, J=5.9 Hz), 4.70 (1H, q, J=3.9 Hz), 4.50 (1H, p, J=7.2 Hz),3.84-3.77 (1H, m), 3.71-3.63 (1H, m), 1.41 (3H, d, J=7.0 Hz); LC/MS:m/z=441.2 [M+H]⁺.

Example 7 Synthesis of(S)-2-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide(Compound Example No. 11)

A mixture of compound 27 (2.1 g, 10.9 mmol), compound 28 (2.4 g), andCs₂CO₃ (3.5 g, 10.9 mmol) in DMF (14 mL) was heated at 100° C. for 4hours. After cooling to room temperature, the mixture was diluted withwater (100 mL) and extracted with EtOAc (3×100 mL). The combined organiclayer was washed with brine, concentrated and purified by columnchromatography (silica gel, EtOAc/hexanes 1/1) to give(4-(3-cyano-4-trifluoromethyl)phenoxy)phenyl)boronic acid (29) (pinksolid, 42%). ¹H NMR (400 MHz, CD₃OD): 7.59-7.86 (3H, m), 7.31-7.37 (1H,m), 7.19-7.26 (1H, m), 6.9-7.10 (2H, m).

(S)-2-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide(Compound Example No. 11) was prepared as a white solid using compound9, compound 29, and the synthetic methodology described in the examplesabove. ¹H NMR (400 MHz, CD₃OD): 8.61 (2H, d, J=8.9 Hz), 8.1 (1H, s),7.83 (1H, d, J=8.9 Hz), 7.56 (1H, d, 2.6 Hz), 7.34-7.38 (1H, m),7.16-7.20 (2H, m), 4.74-4.79 (1H, m), 3.88-3.96 (1H, m), 3.74-3.84 (1H,m); LC/MS: m/z=445.1 [M+H]⁺.

Example 8 Synthesis of(S)-6-(1,2-dihydroxyethyl)-2-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)pyrimidine-4-carboxamide(Compound Example No. 19)

A mixture of compound 30 (20 g, 1.05 eq.), compound 28 (1.0 eq.) andK₂CO₃ (2.0 eq.) in DMF/water (300 mL/15 mL) was heated at 85° C. for 14hours. After cooling to room temperature, the mixture was diluted withwater (200 mL) and extracted with EtOAc (3×200 mL). The combined organiclayer was washed with brine, concentrated and purified by columnchromatography (silica gel, EtOAc/hexanes 1/1) to give(4-((5-trifluoromethyl)pyridine-2-yl)oxy)phenyl)boronic acid (31) (11 g,pink solid, 35%). ¹H NMR (400 MHz, CDCl₃): 8.44-8.55 (1H, m), 8.32 (2H,d, J=8.55 Hz), 7.92-8.02 (1H, m), 7.30 (2H, d, J=8.7 Hz), 7.11 (1H, d,J=9.4 Hz).

(S)-6-(1,2-dihydroxyethyl)-2-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)pyrimidine-4-carboxamide(Compound Example No. 19) was prepared as a white solid using compound9, compound 29, and the synthetic methodology described in the examplesabove. ¹H NMR (400 MHz, CD₃OD): 8.54-8.63 (2H, m), 8.38 (, 1H, s),8.0-8.11 (3H, m), 7.18-7.26 (2H, m), 7.07-7.16 (1H, m), 4.74-4.79 (1H,m), 3.88-3.96 (1H, m), 3.74-3.84 (1H, m); LC/MS: m/z=421.1 [M+H]⁺.

Example 9

Representative Compounds of the Invention have been tested in theFLIPR®, FLIPR^(TETRA)®, and/or electrophysiology (EP) assays for sodiumchannel blocking activity, which is described in detail above.Representative values are presented in TABLE 4.

TABLE 4 Evaluation of compounds as sodium channel (Na_(v)) blockersNa_(v)1.7 Activity (μM) Compound FLIPR assay EP assay EP assay ExampleNo. IC₅₀ K_(i) K_(r) 1 0.195 ± 0.020 0.060 ± 0.010 4.475 ± 0.650 2 0.344± 0.040 0.139 ± 0.020 6.570 ± 0.720 3 0.958 ± 0.292 4 0.965 ± 0.260 50.526 ± 0.129 6 0.593 ± 0.122 7 0.089 ± 0.001 0.044 ± 0.010  1.871 ±0.0250 8 0.114 ± 0.061 9 0.067 ± 0.005  0.027 ± 0.0003 1.041 ± 0.230 100.084 ± 0.029 11 0.279 ± 0.112 0.147 ± 0.030 2.013 ± 0.310 12 0.384 ±0.029 0.400 ± 0.090 8.668 ± 0.990 13 0.394 ± 0.019 0.195 ± 0.030 5.147 ±0.360 14 1.916 ± 0.401 15 >20 16 0.593 ± 0.004 0.643 ± 0.190 153.889 ±54.380  17 0.133 ± 0.026 18 0.135 ± 0.028 19 0.325 0.048

Having now fully described this disclosure, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the disclosure or anyembodiment thereof.

Other embodiments of the disclosure will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

All patents and publications cited herein are fully incorporated byreference in their entirety.

The invention claimed is:
 1. A method of treating a disorder responsiveto blockade of Nay 1.7 sodium channels in a mammal suffering from saiddisorder, comprising administering to a mammal in need of such treatmentan effective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof:

wherein W¹ and W² are N and W³ is CR³; or W¹ and W³ are N and W² is CR³;or W² and W³ are N and W¹ is CR³; R¹ is selected from the groupconsisting of hydrogen; alkyl; cycloalkyl, aralkyl; (heterocyclo)alkyl;(heteroaryl)alkyl; (amino)alkyl; (alkylamino)alkyl; (dialkylamino)alkyl;carboxyalkyl; (alkoxycarbonyl)alkyl; (carboxamido)alkyl; (cyano)alkyl;alkoxyalkyl; monohydroxyalkyl; dihydroxyalkyl; and heteroalkyl; whereinthe alkyl and the cycloalkyl group may optionally be substituted; R² isselected from the group consisting of hydrogen and alkyl; or R¹ and R²taken together with the nitrogen atom to which they are attached form a3- to 8-membered optionally substituted heterocyclo; R³ is selected fromthe group consisting of hydrogen; halo; nitro; cyano; hydroxy; amino;alkylamino; dialkylamino; haloalkyl; monohydroxyalkyl; dihydroxyalkyl;alkoxy; haloalkoxy; and alkoxyalkyl; R⁴ is C₂₋₆ dihydroxyalkyl; A¹ isselected from the group consisting of optionally substituted aryl andoptionally substituted heteroaryl; X is selected from the groupconsisting of —O—; —S—; —SO—; —SO₂—; —(CR^(5a)R^(5b))_(m)—; —NR⁶—;—SO₂NR⁷—; and —NR⁷SO₂—; each R^(5a) and R^(5b), which can be identicalor different, is selected from the group consisting of hydrogen; halo;and alkyl; m is 0, 1, 2, or 3; R⁶ is selected from the group consistingof hydrogen and alkyl; R⁷ is selected from the group consisting ofhydrogen and alkyl; and A² is selected from the group consisting ofoptionally substituted aryl and optionally substituted heteroaryl.
 2. Amethod for treating pain anesthesia in the mammal, comprisingadministering to a mammal in need of such treatment an effective amountof a compound of Formula I, or a pharmaceutically acceptable salt,solvate, or prodrug thereof:

wherein: W¹ and W² are N and W³ is CR³; or W¹ and W³ are N and W² isCR³; or W² and W³ are N and W¹ is CR³; R¹ is selected from the groupconsisting of hydrogen; alkyl; cycloalkyl, aralkyl; (heterocyclo)alkyl;(heteroaryl)alkyl; (amino)alkyl; (alkylamino)alkyl; (dialkylamino)alkyl;carboxyalkyl; (alkoxycarbonyl)alkyl; (carboxamido)alkyl; (cyano)alkyl;alkoxyalkyl; monohydroxyalkyl; dihydroxyalkyl; and heteroalkyl; whereinthe alkyl and the cycloalkyl group may optionally be substituted; R² isselected from the group consisting of hydrogen and alkyl; or R¹ and R²taken together with the nitrogen atom to which they are attached form a3- to 8-membered optionally substituted heterocyclo; R³ is selected fromthe group consisting of hydrogen; halo; nitro; cyano; hydroxy; amino;alkylamino; dialkylamino; haloalkyl; monohydroxyalkyl; dihydroxyalkyl;alkoxy; haloalkoxy; and alkoxyalkyl; R⁴ is C₂₋₆ dihydroxyalkyl: A¹ isselected from the group consisting of optionally substituted aryl andoptionally substituted heteroaryl; X is selected from the groupconsisting of —O—; —S—; —SO—; —SO₂—; —(CR^(5a)R^(5b))_(m)—; —NR⁶—;—SO₂NR⁷—; and —NR⁷SO₂; each R^(5a) and R^(5b), which can be identical ordifferent, is selected from the group consisting of hydrogen; halo; andalkyl; m is 0, 1, 2, or 3; R⁶ is selected from the group consisting ofhydrogen and alkyl; R⁷ is selected from the group consisting of hydrogenand alkyl; and A² is selected from the group consisting of optionallysubstituted aryl and optionally substituted heteroaryl.
 3. The method ofclaim 2, wherein said method is for preemptive or palliative treatmentof pain.
 4. The method of claim 2, wherein said pain is selected fromthe group consisting of chronic pain, inflammatory pain, neuropathicpain, acute pain, and surgical pain.
 5. A method of modulating sodiumchannels in a mammal, comprising administering to the mammal at leastone compound of Formula I, or a pharmaceutically acceptable salt,solvate, or prodrug thereof:

wherein W¹ and W² are N and W³ is CR³; or W¹ and W³ are N and W² is CR³;or W² and W³ are N and W¹ is CR³; R¹ is selected from the groupconsisting of hydrogen; alkyl; cycloalkyl, aralkyl; (heterocyclo)alkyl;(heteroaryl)alkyl; (amino)alkyl; (alkylamino)alkyl; (dialkylamino)alkyl;carboxyalkyl; (alkoxycarbonyl)alkyl; (carboxamido)alkyl; (cyano)alkyl;alkoxyalkyl; monohydroxyalkyl; dihydroxyalkyl; and heteroalkyl; whereinthe alkyl and the cycloalkyl group may optionally be substituted; R² isselected from the group consisting of hydrogen and alkyl; or R¹ and R²taken together with the nitrogen atom to which they are attached form a3- to 8-membered optionally substituted heterocyclo; R³ is selected fromthe group consisting of hydrogen; halo; nitro; cyano; hydroxy; amino;alkylamino; dialkylamino; haloalkyl; monohydroxyalkyl; dihydroxyalkyl;alkoxy; haloalkoxy; and alkoxyalkyl; R⁴ is C₂₋₆ dihydroxyalkyl; A¹ isselected from the group consisting of optionally substituted aryl andoptionally substituted heteroaryl; X is selected from the groupconsisting of —S—; —S—; —SO—; —SO₂—; —(CR^(5a)R^(5b))_(m)—; NR⁶—; and—SO₂NR⁷—; and —NR⁷SO₂; each R^(5a) and R^(5b), which can be identical ordifferent, is selected from the group consisting of hydrogen; halo; andalkyl; m is 0, 1, 2, or R⁶ is selected from the group consisting ofhydrogen and alkyl; R⁷ is selected from the group consisting of hydrogenand alkyl; and A² is selected from the group consisting of optionallysubstituted aryl and optionally substituted heteroaryl.
 6. The method ofclaim 5, wherein the Nav1.7 sodium channel is modulated.
 7. The methodof claim 2, wherein said compound is a compound of Formula II:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof,wherein: R^(8a) and R^(8b) are each independently selected from thegroup consisting of hydrogen; alkyl; halo; nitro; cyano; hydroxy; amino;alkylamino; dialkylamino; haloalkyl; monohydroxyalkyl; dihydroxyalkyl;alkoxy; haloalkoxy; carboxy; and alkoxycarbonyl.
 8. The method of claim7, wherein said compound is a compound of Formula III:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 9.The method of claim 8, wherein A¹ is selected from the group consistingof:

wherein; R^(9a), R^(9b), R^(10a), R^(10b), R^(11a), R^(11b), R^(12a),and R^(12b) are each independently selected from the group consisting ofhydrogen; alkyl; halo; nitro; cyano; hydroxy; amino; alkylamino;dialkylamino; haloalkyl; monohydroxyalkyl; dihydroxyalkyl; alkoxy;haloalkoxy; carboxy; and alkoxycarbonyl, or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof.
 10. The method of claim 8,wherein: W¹ and W² are N and W³ is CR³; and R³ is hydrogen, or apharmaceutically acceptable salt, solvate, or prodrug thereof.
 11. Themethod of claim 8, wherein: W¹ and W³ are N and W² is CR³; and R³ ishydrogen, or a pharmaceutically acceptable salt, solvate, or prodrugthereof.
 12. The method of claim 8, wherein R^(8a) and R^(8b) arehydrogen, or a pharmaceutically acceptable salt, solvate, or prodrugthereof.
 13. The method of claim 8, wherein R¹ is selected from thegroup consisting of hydrogen; alkyl; carboxyalkyl;(alkoxycarbonyl)alkyl; and (carboxamido)alkyl; and R² is hydrogen, or apharmaceutically acceptable salt, solvate, or prodrug thereof.
 14. Themethod of claim 8, wherein R¹ and R² are hydrogen, or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof.
 15. The method of claim 8,wherein R⁴ is a C₂₋₄ dihydroxyalkyl, or a pharmaceutically acceptablesalt, solvate, or prodrug thereof.
 16. The method of claim 2, whereinsaid compound is a compound of Formula V:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 17.The method of claim 2, wherein said compound is a compound of FormulaVI:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 18.The method of claim 2, wherein said compound is a compound of FormulaVII:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 19.The method of claim 2, wherein said compound is a compound of FormulaVIII:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 20.The method of claim 2, wherein said compound is selected from the groupconsisting of:(S)-6-(1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide;(R)-6-(1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide;(S)-2-(4-(4-cyanophenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide;(R)-2-(4-(4-cyanophenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide;(S)-2-(4-(4-cyano-2-(trifluoromethyl)phenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide;(R)-2-(4-(4-cyano-2-(trifluoromethyl)phenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide;(R)-2-(4-(5-chloro-2-fluorophenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide;(S)-2-(4-(5-chloro-2-fluorophenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide;(R)-2-(4-(4-chloro-2-fluorophenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide;(S)-2-(4-(4-chloro-2-fluorophenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide;(S)-2-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide;(R)-2-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide;(S)-2-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-6-(1,2-dihydroxyethyl)pyrimidine-4-carboxamide;(S)-methyl2-(6-((S)-1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamido)propanoate;(S)-2-(6-((S)-1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamido)propanoicacid;N—((S)-1-amino-1-oxopropan-2-yl)-6-((S)-1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide;(S)-6-(1,2-dihydroxyethyl)-2-(4-(4-(trifluoromethyl)phenoxy)phenyl)pyrimidine-4-carboxamide;(R)-6-(1,2-dihydroxyethyl)-2-(4-(4-(trifluoromethyl)phenoxy)phenyl)pyrimidine-4-carboxamide;(S)-6-(1,2-dihydroxyethyl)-2-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)pyrimidine-4-carboxamide;(R)-4-(1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)pyrimidine-2-carboxamide;and(S)-4-(1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)pyrimidine-2-carboxamide,or a pharmaceutically acceptable salt, solvate, or prodrug thereof.